EP1135371A1 - Beta-alanine derivatives as alpha 4 integrin inhibitors - Google Patents

Beta-alanine derivatives as alpha 4 integrin inhibitors

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Publication number
EP1135371A1
EP1135371A1 EP99973020A EP99973020A EP1135371A1 EP 1135371 A1 EP1135371 A1 EP 1135371A1 EP 99973020 A EP99973020 A EP 99973020A EP 99973020 A EP99973020 A EP 99973020A EP 1135371 A1 EP1135371 A1 EP 1135371A1
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Prior art keywords
group
optionally substituted
amino
groups
acid
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German (de)
French (fr)
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John Robert Porter
John Clifford Head
Graham John Warrellow
Sarah Catherine Archibald
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UCB Celltech Ltd
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Celltech R&D Ltd
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C2601/14—The ring being saturated

Abstract

Alkanoic acid derivatives of formula (1) are described: Ar1(Alka)rL?1Ar2CH(R1)C(Ra)(Ra'¿)R wherein Ar1 is an optionally substituted aromatic or heteroaromatic group; L1 is a covalent bond or a linker atom or group; Ar2 is an optionally substituted phenylene or nitrogen-containing six-membered heteroarylene group; R is a carboxylic acid (-CO¿2?H) or a derivative thereof; and the salts, solvates, hydrates and N-oxides thereof. The compounds are able to inhibit the binding of α4 integrins to their ligands and are of use in the prophylaxis and treatment of immune or inflammatory disorders.

Description

/J-ALANINE DERIVATIVES AS α4 INTEGRIN INHIBITORS
This invention relates to a series of alkanoic acid derivatives, to processes for their preparation, and to their use in medicine.
Over the last few years it has become increasingly clear that the physical interaction of inflammatory leukocytes with each other and other cells of the body plays an important role in regulating immune and inflammatory responses [Springer, T A. Nature. 346. 425. (1990); Springer, T. A. Cell 76, 301 , (1994)]. Many of these interactions are mediated by specific cell surface molecules collectively referred to as cell adhesion molecules.
The adhesion molecules have been sub-divided into different groups on the basis of their structure. One family of adhesion molecules which is believed to play a particularly important role in regulating immune and inflammatory responses is the integrin family. This family of cell surface glycoproteins has a typical non-covalently linked heterodimer structure. At least 14 different integrin alpha chains and 8 different integrin beta chains have been identified [Sonnenberg, A. Current Topics in Microbiology and Immunology, 184. 7, (1993)]. The members of the family are typically named according to their heterodimer composition although trivial nomenclature is widespread in this field. Thus the integrin termed α4β1 consists of the integrin alpha 4 chain associated with the integrin beta 1 chain, but is also widely referred to as Very Late Antigen 4 or VLA4. Not all of the potential pairings of integrin alpha and beta chains have yet been observed in nature and the integrin family has been subdivided into a number of subgroups based on the pairings that have been recognised [Sonnenberg, A. ibid\.
The importance of cell adhesion molecules in human leukocyte function has been further highlighted by a genetic deficiency disease called Leukocyte Adhesion Deficiency (LAD) in which one of the families of leukocyte integrins is not expressed [Marlin, S. D. et al J. Exp. Med. 164. 855 (1986)]. Patients with this disease have a reduced ability to recruit leukocytes to inflammatory sites and suffer recurrent infections which in extreme cases may be fatal.
The potential to modify adhesion molecule function in such a way as to beneficially modulate immune and inflammatory responses has been extensively investigated in animal models using specific monoclonal antibodies that block various functions of these molecules [e.g. Issekutz, T. B. J. Immunol. 3394, (1992); Li, Z. §t_al Am. J. Physiol. 263, L723, (1992); Binns, R. M. et al J. Immunol. 157. 4094, (1996)]. A number of monoclonal antibodies which block adhesion molecule function are currently being investigated for their therapeutic potential in human disease.
One particular integrin subgroup of interest involves the α4 chain which can pair with two different beta chains β1 and β7 [Sonnenberg, A. ibid]. The α4β1 pairing occurs on many circulating leukocytes (for example lymphocytes, monocytes and eosinophils) although it is absent or only present at low levels on circulating neutrophils. α4β1 binds to an adhesion molecule (Vascular Cell Adhesion Molecule-1 also known as VCAM-1 ) frequently up-regulated on endothelial cells at sites of inflammation [Osborne, L. Cell, 62, 3, (1990)]. The molecule has also been shown to bind to at least three sites in the matrix molecule fibronectin [Humphries, M. J. et al. Ciba Foundation Symposium, 189. 177, (1995)]. Based on data obtained with monoclonal antibodies in animal models it is believed that the interaction between α4β1 and ligands on other cells and the extracellular matrix plays an important role in leukocyte migration and activation [Yednock, T. A. et al. Nature, 356, 63, (1992); Podolsky, D. K. et al. J. Clin. Invest. 92, 373, (1993); Abraham, W. M. et al. J. Clin. Invest. 93, 776, (1994)].
The integrin generated by the pairing of α4 and β7 has been termed LPAM- 1 [Holzmann, B and Weissman, I. EMBO J. 8, 1735, (1989)] and like α4β1 , binds to VCAM-1 and fibronectin. In addition, α4β7 binds to an adhesion molecule believed to be involved in the homing of leukocytes to mucosal tissue termed MAdCAM-1 [Berlin, C. et al. Cell, 74, 185, (1993)]. The interaction between α4β7 and MAdCAM-1 may also be important at sites of inflammation outside of mucosal tissue [Yang, X-D. et al, PNAS, 91, 12604 (1994)].
Regions of the peptide sequence recognised by α4β1 and α4β7 when they bind to their ligands have been identified. 4β1 seems to recognise LDV, IDA or REDV peptide sequences in fibronectin and a QIDSP sequence in VCAM-1 [Humphries, M. J. et al. ibid] whilst α4β7 recognises a LDT sequence in MAdCAM-1 [Briskin, M. J. et al. J. Immunol. 156, 719, (1996)]. There have been several reports of inhibitors of these interactions being designed from modifications of these short peptide sequences [Cardarelli, P. M. sLal J. Biol. Chem. 269, 18668, (1994); Shroff, H. N. Bioorganic. Med. Chem. Lett. 6, 2495, (1996); Vanderslice, P. J. Immunol. 158, 1710, (1997)]. It has also been reported that a short peptide sequence derived from the α4β 1 binding site in fibronectin can inhibit a contact hypersensitivity reaction in a trinitrochlorobenzene sensitised mouse [Ferguson, T. A. stsl, PNAS 88, 8072, (1991)].
Since the alpha 4 subgroup of integrins are predominantly expressed on leukocytes their inhibition can be expected to be beneficial in a number of immune or inflammatory disease states. However, because of the ubiquitous distribution and wide range of functions performed by other members of the integrin family it is very important to be able to identify selective inhibitors of the alpha 4 subgroup.
We have now found a group of compounds which are potent and selective inhibitors of α4 integrins. Members of the group are able to inhibit 4 integrins such as α4β1 and/or α4β7 at concentrations at which they generally have no or minimal inhibitory action on α integrins of other subgroups. The compounds are thus of use in medicine, for example in the prophylaxis and treatment of immune or inflammatory disorders as described hereinafter.
Thus according to one aspect of the invention we provide a compound of formula (1): Arl (Alka)rL1Ar2CH(R'' )C(Ra)(Ra,)R (1) wherein
Ar1 is an optionally substituted aromatic or heteroaromatic group; L1 is a covalent bond or a linker atom or group selected from -CON(R2)- [where R2 is a hydrogen atom or a Chalky! group], -SO2N(R2)-, -C(O)O-, -N(R2)- or -O-;
Ar2 is an optionally substituted phenylene or nitrogen-containing six- membered heteroarylene group;
R1 is a group selected from -NHCOR3 [where R3 is an optionally substituted aliphatic, heteroaliphatic, cycloaliphatic, polycycloaliphatic, heterocycloaliphatic, heteropolycycloaliphatic, aromatic or heteroaromatic group], -NHSO2R3, -NHR3, -NHC(O)OR3, -NHCSR3, -NHCON(R3)(R3a) [where R3a is a hydrogen atom or a group R3 and R3 and R3a are the same or different], -NHSO2N(R3)(R3a), -NHCSN(R3)(R3a), -CON(R3)(R3a) or -CSN(R3)(R3a); Ra and Ra' which may be the same or different is each independently selected from a hydrogen or halogen atom or an optionally substituted straight or branched alkyl, alkenyl or alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, or -(Alk )mRb group (in which Alkb is a Ci-3alkylene chain, m is zero or the integer 1 and Rb is a -OH, -SH, -NO2, -CN, -CO2H, -CO2Rc, (where Rc is an optionally substituted straight or branched Ci-6alkyl group), -SO3H, -SORc, -SO2Rc, -SO3Rc, -OCO2Rc, -C(0)H, -C(O)Rc, -OC(O)Rc, -C(S)RC, -NRdRe [where Rd and Re which may be the same or different is each a hydrogen atom or an optionally substituted straight or branched alkyl group], -C(O)N(Rd)(Re), -OC(O)N(Rd)(Re), -N(Rd )C(O)Re, -CSN(Rd)(Re), -N(R)dC(S)Re, -SO2 N(Rd)(Re), -N(Rd)SO2Re,
-N(Rd)CON(Re)(Rf) [where Rf is a hydrogen atom or an optionally substituted straight or branched alkyl group], -N(Rd)C(S)N(Re)(Rf) or -N(Rd)SO2N(Re)(Rf) group). Alka is an optionally substituted aliphatic or heteroaliphatic chain; r is zero or the integer 1 ;
R is a carboxylic acid (-CO2H) or a derivative thereof; and the salts, solvates, hydrates and N-oxides thereof.
It will be appreciated that compounds of formula (1 ) may have one or more chiral centres, and exist as enantiomers or diastereomers. The invention is to be understood to extend to all such enantiomers, diastereomers and mixtures thereof, including racemates. Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise.
In the compounds of the invention as represented by formula (1 ) and the more detailed description hereinafter certain of the general terms used in relation to substituents are to be understood to include the following atoms or groups unless specified otherwise.
Thus as used herein the term "straight or branched alkyl", whether present as a group or part of a group includes straight or branched C-i-βalkyl groups, for example C-|-4alkyl groups such as methyl, ethyl, n-propyl, i- propyl or t-butyl groups. Similarly, the terms "straight or branched alkenyl" or "straight or branched alkynyl" are intended to mean C2-6alkenyl or C2- βa'kynyl groups such as C2-4alkenyl or C2-4alkynyl groups.
The term "halogen atom" is intended to include fluorine, chlorine, bromine or iodine atoms.
The term "straight or branched haloalkyl" is intended to include the alkyl groups just mentioned substituted by one, two or three of the halogen atoms just described. Particular examples of such groups include -CF3, -CCI3, -CHF2- -CHCI2, -CH2F, and -CH2CI groups.
The term "straight or branched alkoxy" as used herein is intended to include straight or branched C-i-βalkoxy e.g. Ci-4alkoxy such as methoxy, ethoxy, n-propoxy, i-propoxy and t-butoxy. "Haloalkoxy" as used herein includes any of those alkoxy groups substituent by one, two or three halogen atoms as described above. Particular examples include -OCF3, -OCCI3, -OCHF2, -OCHCI2, -OCH2F and -OCH2CI groups.
As used herein the term "straight or branched alkylthio" is intended to include straight or branched C-|_6alkylthio, e.g. Cι-4alkylthio such as methylthio or ethylthio groups. In the compounds of formula (1 ), derivatives of the carboxylic acid group R include carboxylic acid esters and amides. Particular esters and amides include -CO2Alk1 and -CONR5R6 groups as described herein.
When Alka is present in compounds of formula (1 ) as an optionally substituted aliphatic or heteroaliphatic chain it may be for example any divalent chain corresponding to the below-mentioned aliphatic or heteroaliphatic groups described for R3.
Aromatic groups represented by the group Ar1 in compounds of the invention include for example monocyclic or bicyclic fused ring Cβ-12 aromatic groups, such as phenyl, 1 - or 2-naphthyl, 1 - or 2- tetrahydronaphthyl, indanyl or indenyl groups.
Heteroaromatic groups represented by the group Ar1 in the compounds of formula (1 ) include for example C1-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups. Monocyclic heteroaromatic groups include for example five- or six- membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include for example eight- to thirteen-membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Particular examples of heteroaromatic groups of these types include pyrrolyl, furyl, thienyl, imidazolyl, N-Ci-βalkylimidazolyl. oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,3- oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,3,4- thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1 ,3,5-triazinyl, 1 ,2,4- triazinyl, 1 ,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, benzothienyl, benzotriazolyl, indolyl, indolinyl, isoindolyl, indazolinyl, benzimidazolyl, imidazo[1 ,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyhdo[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]- pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7, 8-tetrahydroisoquinolinyl, and imidyl, e.g. succinimidyl, phthalimidyl, or naphthalimidyl such as 1 ,8-naphthalimidyl.
Each aromatic or heteroaromatic group represented by the group Ar1 may be optionally substituted on any available carbon or, when present, nitrogen atom. One, two, three or more of the same or different substituents may be present and each substituent may be selected for example from an atom or group -L2(Alk)tL3(R4)u in which L2 and L3, which may be the same or different, is each a covalent bond or a linker atom or group, t is zero or the integer 1 , u is an integer 1 , 2 or 3, Alk is an aliphatic or heteroaliphatic chain and R4 is a hydrogen or halogen atom or a group selected from Ci-βalkyl, -OR5 [where R5 is a hydrogen atom or an optionally substitued C-i-βalkyl group], -SR5, -NR5R6 [where R6 is as just defined for R5 and may be the same or diferent], -NO2, -CN, -CO2R5, -SO3H, -SO3R5, -SOR5, -SO2R5, -OCO2R5, -CONR5R6, -OCONR5R6, -CSNR5R6, -COR5, -OCOR5, -N(R5)COR6, -N(R5)CSR6, -SO2N(R5)(R6), -N(R5)SO2R6, N(R5)CON(R6)(R7) [where R7 is a hydrogen atom or an optionally substituted C-|-6alkyl group], -N(R5)CSN(R6)(R7) or -N(R5)SO2N(R6)(R7), provided that when t is zero and each of L2 and L3 is a covalent bond then u is the integer 1 and R4 is other than a hydrogen atom
When L2 and/or L3 is present in these sustituents as a linker atom or group it may be any divalent linking atom or group. Particular examples include -O- or -S- atoms or -C(O)-, -C(0)0-, -OC(O)-, -C(S)-, -S(O)-, -S(O)2-, -N(R8)- [where R8 is a hydrogen atom or an optionally substituted Ci-ealkyl group], -CON(R8)-, -OC(O)N(R8)-, -CSN(R8)-, -N(R8)CO-, -N(R8)C(O)O-, -N(R8)CS-, -S(O)2N(R8)-, -N(R8)S(O)2-, -N(R8)CON(R8)-, -N(R8)CSN(R8)-, or -N(R8)SO2N(R8)- groups. Where the linker group contains two R8 substituents, these may be the same or different.
When Rc, Rd, Re, Rf, R4, R5, R6, R7 and/or R8 is present as a C-i-βalkyl group it may be a straight or branched Ci-ealk l group, e.g. a Ci-3alkyl group such as a methyl or ethyl group. Optional substituents which may be present on such groups include for example one, two or three substituents which may be the same or different selected from halogen atoms, for example fluorine, chlorine, bromine or iodine atoms, or hydroxy or C - βalkoxy e.g. methoxy or ethoxy groups.
When Alk is present as an aliphatic or heteroaliphatic chain it may be for example any divalent chain corresponding to the below-mentioned aliphatic or heteroaliphatic group described for R3.
Halogen atoms represented by R4 in the optional Ar1 substituents include fluorine, chlorine, bromine, or iodine atoms.
Examples of the substituents represented by -L2(Alk)tL3(R )u when present in Ar1 groups in compounds of the invention include atoms or groups -L2AlkL3R4, -L2AlkR4, -L2R4 and -AlkR4 wherein L2, Alk, L3 and R4 are as defined above. Particular examples of such substituents include -L2CH2L3R4, -L2CH(CH3)L3R4, -L2CH2(CH2)2 3R4, -L2CH2R4, -L2CH(CH3)R4, -L2(CH2)2R4, -CH2R4, -CH(CH3)R4 , -(CH2)2R4 and -R4 groups.
Thus Ar1 in compounds of the invention may be optionally substituted for example by one, two, three or more halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, and/or Ci-ealkyl, e.g. methyl, ethyl, n-propyl, i- propyl, n-butyl or t-butyl, Cι-6alkylamino, e.g. methylamino or ethylamino, Cι-6hydroxyalkyl, e.g. hydroxymethyl, hydroxyethyl or -C(OH)(CF3)2, carboxyCi-βalkyl, e.g. carboxyethyl, Ci-εalkylthio e.g. methylthio or ethylthio, carboxyC -βalkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, Ci-βalkoxy, e.g. methoxy or ethoxy, optionally substituted C6-i2arylCi-6alkyloxy e.g. benzyloxy, hydroxyCi-βalkoxy, e.g. 2-hydroxyethoxy, haloCi-ealkyl, e.g. -CF3, -CHF2, CH2F, haloCi-βalkoxy, e.g. -OCF3, -OCHF2, -OCH2F, Ci-βalkylamino, e.g. methylamino or ethylamino, amino (-NH2), aminoCi-βalkyl, e.g. aminomethyl or aminoethyl, Ci-δdialkylamino, e.g. dimethylamino or diethylamino, Ci- 6alkylaminoCi-6alkyl, e.g. ethyiaminoethyl, C -6 dialkylaminoCι_6alkyl, e.g. diethylaminoethyl, aminoCi-ealkoxy, e.g. aminoethoxy, hydroxyC _6alkyl- amino e.g. hydroxyethylamino or hydroxypropylamino, Ci-βalkylaminoC - βalkoxy, e.g. methylaminoethoxy, C -6dialkylaminoCi -6alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, diisopropylaminoethoxy, or dimethylaminopropoxy, nitro, cyano, amidino, hydroxyl (-OH), formyl [HC(O)-], carboxyl (-CO2H), -CO2Alk1 [where Alk1 is as defined below], C -6 alkanoyl e.g. acetyl, thiol (-SH), thioCi-βalkyl, e.g. thiomethyl or thioethyl, thioCι-6alkylC6-i2aryl e.g. thiobenzyl, sulphonyl (-SO3H), -SO3Alk1 , Cι-6alkylsulphinyl e.g. methylsulphinyl or ethylsulphinyl, Cι- 6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (-SO2NH2), C1-6 alkylaminosulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, Cι-6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylamino- sulphonyl, optionally substituted phenylaminosulphonyl, carboxamido (-CONH2), Ci-6alkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, Cι_6dialkylaminocarbonyl, e.g. dimethylamino- carbonyl or diethylaminocarbonyl, aminoCi-6alkylaminocarbonyl, e.g. aminoethylaminocarbonyl, Ci-6dialkylaminoCi-6alkylaminocarbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino, Ci-βalkylamino- carbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonyl- amino, Ci-6dialkylaminocarbonylamino, e.g. dimethylaminocarbonylamino or diethylaminocarbonylamino, Ci-6alkylaminocabonylCι-6alkylamino, e.g. methylaminocarbonylmethylamino, aminothiocarbonylamino, Ci-βalkyl- aminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, Cι-6dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, Ci- 6alkylaminothiocarbonylCi-6alkylamino, e.g. ethylaminothiocarbonyl- methylamino, Ci-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, Ci-6dialkylsulphonylamino, e.g. dimethylsulphonyl- amino or diethylsulphonylamino, aminosulphonylamino (-NHSO2NH2), Ci- 6alkylamino-sulphonylamino, e.g. methylaminosulphonylamino or ethyl- aminosulphonylamino, C -6dialkylaminosulphonylamino, e.g. dimethyl- aminosulphonylamino or diethylaminosulphonylamino, Ci-βalkanoylamino, e.g. acetylamino, aminoCi-6alkanoylamino e.g. aminoacetylamino, Cι- 6dialkylaminoC -6alkanoylamino, e.g. dimethylaminoacetylamino, Ci- 6alkanoylaminoCi-6alkyl, e.g. acetylaminomethyl, Ci-6alkanoylaminoCi- βalkylamino, e.g. acetamidoethylamino, Cι_6alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino groups. When the group R3 is present in compounds of formula (1 ) as an optionally substituted aliphatic group it may be an optionally substituted C1-10 aliphatic group. Particular examples include optionally substituted straight or branched chain C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl groups.
Heteroaliphatic groups represented by the group R3 include the aliphatic groups just described but with each group additionally containing one, two, three or four heteroatoms or heteroatom-containing groups. Particular heteroatoms or groups include atoms or groups L4 where L4 is as defined above for L2 when L2 is a linker atom or group. Each L4 atom or group may interrupt the aliphatic group, or may be positioned at its terminal carbon atom to connect the group to an adjoining atom or group.
Particular examples of aliphatic groups represented by the group R3 include optionally substituted -CH3 , -CH2CH3, -CH(CH3)2, -(CH2)2CH3, -CH(CH3)CH3, -(CH2)3CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -(CH2)4CH3, -(C H2)5C H 3, -CHCH2, -CHCHCH3 , -C H2CHCH2, -CHCHCH2C H 3, -CH2CHCHCH3, -(CH2)2CHCH2, -CCH, -CCCH3 , -CH2CCH, -CCCH2CH3, -CH2CCCH3, or -(CH2)2CCH groups. Where appropriate each of said groups may be optionally interrupted by one or two atoms and/or groups L4 to form an optionally substituted heteroaliphatic group. Particular examples include optionally substituted -L4CH3, -CH2L4CH3 , -L4CH2CH3, -CH2L4CH2CH3, -(CH2)2L CH3, -L (CH2)3CH3 and -(CH2)2 4CH2CH3 groups.
The optional substituents which may be present on aliphatic or heteroaliphatic chains represented by R3 include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or hydroxy, Ci-βalkoxy, e.g. methoxy or ethoxy, thiol, Ci-βalkylthio e.g. methylthio or ethylthio, amino or substituted amino groups. Substituted amino groups include -NHR9 and -N(R9)2 groups where R9 is an optionally substituted straight or branched Ci-ealkyi group as defined above for R4. Where two R9 groups are present these may be the same or different. Particular examples of substituted groups represented by R3 include those specific groups just described substituted by one, two, or three halogen atoms such as fluorine atoms, for example groups of the type -CHCF3, -CH(CF3)2, -CH2CH2CF3, -CH2CH(CF3)2 and -C(CF3)2CH3.
Optionally substituted cycloaliphatic groups represented by the group R3 in compounds of the invention include optionally substituted C3-10 cycloaliphatic groups. Particular examples include optionally substituted C3-10 cycloalkyl, e.g. C3-7 cycloalkyl or C3.10 cycloalkenyl, e.g C3-7 cycloalkenyl groups.
Optionally substituted heterocycloaliphatic groups represented by the group R3 include optionally substituted C3-ioheterocycloaliphatic groups. Particular examples include optionally substituted C3-ιoheterocycloalkyl, e.g. C3-7 heterocycloalkyl, or C3_ιoheterocycloalkenyl, e.g. C3-7 hetercycloalkenyl groups, each of said groups containing one, two, three or four heteroatoms or heteroatom-containing groups L4 as defined above.
Optionally substituted polycycloaliphatic groups represented by the group R3 include optionally substitued C7- 0 bi- or tricycloalkyl or C -iobi- or tricycloalkenyl groups. Optionally substituted heteropolycycloaliphatic groups represented by the group R3 include the optionally substituted polycycloalkyl groups just described, but with each group additionally containing one, two, three or four L4 atoms or groups.
Particular examples of cycloaliphatic, polycycloaliphatic, heterocycloaliphatic and heteropolycycloaliphatic groups represented by the group R3 include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1 -yl, 2-cyclopenten-1 -yl, 3- cyclopenten-1 -yl, adamantyl, norbornyl, norbornenyl, tetrahydrofuranyl, pyrroline, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinone, oxazolidinyl, oxazolidinone, dioxolanyl, e.g. 1 ,3-dioxolanyl, imidazolinyl, e.g. 2- imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl, piperidinone, 1 ,4-dioxanyl, morpholinyl, morpholinone, 1 ,4-dithianyl, thiomorpholinyl, piperazinyl, 1 ,3,5-trithianyl, oxazinyl, e.g. 2H-1 ,3-, 6H-1,3-, 6H-1.2-, 2H-1 ,2- or 4H-1 ,4- oxazinyl, 1 ,2,5-oxathiazinyl, isoxazinyl, e.g. o- or p-isoxazinyl, oxathiazinyl, e.g. 1 ,2,5 or 1 ,2,6-oxathiazinyl, or 1 ,3,5,- oxadiazinyl groups.
The optional substituents which may be present on the cycloaliphatic, polycycloaliphatic, heterocycloaliphatic or heteropolycycloaliphatic groups represented by the group R3 include one, two, three or more substituents each selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or Ci-βalkyl, e.g. methyl or ethyl, haloCi-ealkyl, e.g. halomethyl or haloethyl such as difluoromethyl or trifluoromethyl, optionally substituted by hydroxyl, e.g. -C(OH)(CF3)2, hydroxyl, Cι-6alkoxy, e.g. methoxy or ethoxy, haloCi-βalkoxy, e.g. halomethoxy or haloethoxy such as difluoromethoxy or trifluoromethoxy, thiol, Ci-βalkylthio e.g. methylthio or ethylthio, or -(Alk2)vR10 groups in which Alk2 is a straight or branched C1-3 alkylene chain, v is zero or an integer 1 and R10 is a -OH, -SH, -N(R11)2, -CN, -CO2R11 , -NO2, -CON(R11)2, -CSN(R11)2, -OC(O)N(R11)2, -C(O)H, -COR1 1, -OCO2R11 , -OC(O)R11, -C(S)R11, -CSN(R11)2, -N(R 1)COR11, -N(R11)CSR11, -SO3H, -SOR 1, -SO2R11, -SO3R1 1 , -SO2N(R11)2, -N(R11)SO2R1 1 , -N(R11)CON(R11)2,
-N(R11)CSN(R 1)2 or -N(R11)SO2N(R1 1)2 [in which R1 1 is an atom or group as defined herein for R8 or an optionally substituted cycloaliphatic or heterocycloaliphatic group as previously defined for R3] aromatic or heteroaromatic group. Where two R1 1 atoms or groups are present in these substituents these may be the same or different.
Additionally, when the group R3 is a heterocycloaliphatic group containing one or more nitrogen atoms each nitrogen atom may be optionally substituted by a group -(L5)p(Alk3)qR12 in which L5 is -C(O)-, -C(O)O-, -C(S)-, -S(O)-, -S(O)2-, -CON(R1 1 )-, -CSN(R1 1 )-, -SON(R1 )- or SO2N(R1 1 )-; p is zero or an integer 1 ; Alk3 is an optionally substituted aliphatic or heteroaliphatic chain; q is zero or an integer 1 ; and R12 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group.
Optionally substituted aliphatic or heteroaliphatic chains represented by Alk3 include those optionally substituted chains described above for R3. Cycloaliphatic, heterocycloaliphatic, polycyloaliphatic or polyheterocyclo- aliphatic groups represented by R12 include those groups just described for the group R3. Optional substituents which may be present on these groups include those described above in relation to R3 aliphatic and heteroaliphatic chains.
Optionally substituted aromatic and heteroaromatic groups represented by the group R3 in compounds of the invention include those groups as described above in relation to Ar1. The aromatic or heteroaromatic group may be attached to the remainder of the compound of formula (1 ) by any appropriate carbon on hetero e.g. nitrogen atom.
Optional substituents which may be present on the aromatic or heteroaromatic groups represented by the group R3 include one, two, three or more substituents, each selected from an atom or group R13 in which R13 is -R13a or -Alk4(R 3a)m, where R13a is a halogen atom, or an amino (- NH2), substituted amino, nitro, cyano, amidino, hydroxyl (-OH), substituted hydroxyl, formyl, carboxyl (-CO2H), esterified carboxyl, thiol (-SH), substituted thiol, -COR14 [where R14 is an -Alk (R13a)mι aryl or heteroaryl group], -CSR1 4, -SO3H, -SOR1 4, -SO2R1 4 -SO2NH2, -SO2NHR14 SO2N(R 4)2, -CONH2, -CSNH2, -CONHR14, -CSNHR14, -CON[R14]2, -CSN(R14)2, -N(R1 1 )SO2R14, -N(SO2R14)2, -N(R1 1 )SO2NH2, -N(R11)SO2NHR14, -N(R11)SO2N(R1 )2, -N(R 1)COR14, -N(R1 )CONH2, -N(R1 1)CONHR14, -N(R 1)CON(R1 )2, -N(R11)CSNH2, -N(R1 )CSNHR14, -N(R1 )CSN(R14)2, -N(R11)CSR14, -N(R11 )C(O)OR14, -SO2NHet1 [where -NHet1 is an optionally substituted C5-7cyclicamino group optionally containing one or more other -O- or -S- atoms or -N(R11)-, -C(O)- or -C(S)- groups], -CONHet1 , -CSNHet1 , -N(R11)SO2NHet1, - N(R11)CONHet1 , -N(R1 1)CSNHet1 , -SO2N(R1 1)Het2 [where Het2 is an optionally substituted monocyclic C5-7carbocyclic group optionally containing one or more -O- or -S- atoms or -N(R1 1 )-, -C(O)- or -C(S)- groups], -Het2, -CON(R11)Het2, -CSN(R11)Het2, -N(R11)CON(R1 )Het2, -N(R11)CSN(R1 )Het2, aryl or heteroaryl group; Alk4 is a straight or branched Ci-βalkylene, C2- ealkenylene or C2-6alkynylene chain, optionally interrupted by one, two or three -O- or -S- atoms or -S(O)n [where n is an integer 1 or 2] or -N(R15)- groups [where R15 is a hydrogen atom or Ci-βalkyl, e.g. methyl or ethyl group]; and m is zero or an integer 1 , 2 or 3. It will be appreciated that when two R1 1 or R14 groups are present in one of the above substituents, the R 1 or R14 groups may be the same or different.
When in the group -Alk4(R13a)m m is an integer 1 , 2 or 3, it is to be understood that the substituent or substituents R13a may be present on any suitable carbon atom in -Alk4. Where more than one R13a substituent is present these may be the same or different and may be present on the same or different atom in -Alk4. Clearly, when m is zero and no substituent Ri3a js present the alkylene, alkenylene or alkynylene chain represented by Alk4 becomes an alkyl, alkenyl or alkynyl group.
When R13a is a substituted amino group it may be for example a group -NHR14 [where R14 is as defined above] or a group -N(R14)2 wherein each R 4 group is the same or different.
When R13a is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
When R13a is a substituted hydroxyl or substituted thiol group it may be for example a group -OR14 or a -SR14 or -SC(=NH)NH2 group respectively.
Esterified carboxyl groups represented by the group R13a include groups of formula -CO2Alk1 wherein Alk1 is a straight or branched, optionally substituted Ci-salkyl group such as a methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl or t-butyl group; a C6-i2arylCi-8alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or
2-naphthylmethyl group; a C6-i2aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a C6-i2aryloxyCi-8alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1 - naphthyloxymethyl, or 2-naphthyloxymethyl group; an optionally substituted Ci-salkanoyloxyCi-βalkyl group, such as a pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; or a C6-i2aroyloxyCi-8alkyl group such as an optionally substituted benzoyloxyethyl or benzoyloxy- propyl group. Optional substituents present on the Alk1 group include R13a substituents described above.
When Alk4 is present in or as a substituent it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s- butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3- butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three -O- or -S-, atoms or -S(O)-, -S(O)2- or -N(R12)- groups.
Aryl or heteroaryl groups represented by the groups R13a or R1 include mono- or bicyclic optionally substituted Cβ-12 aromatic or C1 -9 heteroaromatic groups as described above for the group Ar1. The aromatic and heteroaromatic groups may be attached to the remainder of the compound of formula (1 ) by any carbon or hetero e.g. nitrogen atom as appropriate.
When -NHet1 or -Het2 forms part of a substituent R13 each may be for example an optionally substituted pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl or thiazolidinyl group. Additionally Het2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group. Optional substituents which may be present on -NHet1 or -Het2 include those substituents as described for R3 cycloaliphatic groups above.
Particularly useful atoms or groups represented by R13 include fluorine, chlorine, bromine or iodine atoms, or Ci-βalkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl, pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, thienyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl, Ci-βalkylamino, e.g. methylamino or ethylamino, Ci-6hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, carboxyCi-βalkyl, e.g. carboxyethyl, Ci-βalkylthio e.g. methylthio or ethylthio, carboxyCi-δalkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, Cι_ εalkoxy, e.g. methoxy or ethoxy, hydroxyCi-βalkoxy, e.g. 2-hydroxyethoxy, optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenylthio e.g. 3,5- dimethoxyphenylthio, or pyridylthio, Cs-7cycloalkoxy, e.g. cyclopentyloxy, haloCi-ealkyl, e.g. trifluoromethyl, haloCi-βalkoxy, e.g. trifluoromethoxy, Cι- βalkylamino, e.g. methylamino, ethylamino or propylamino, optionally substituted C6-i2arylC -6alkylamino e.g. benzylamino, amino (-NH2), aminoC -βalkyl, e.g. aminomethyl or aminoethyl, Cι-6dialkylamino, e.g. dimethylamino or diethylamino, aminoCi-βalkylamino e.g. aminomethyl- amino, aminoethylamino or aminopropylamino, optionally substituted Het1 NCi-6alkylamino e.g. morpholinopropylamino, Ci-6alkylaminoCι-6alkyl, e.g. ethylaminoethyl, Ci-βdialkylaminoCi-βalkyl, e.g. diethylaminoethyl, aminoCi-βalkoxy, e.g. aminoethoxy, Ci-6alkylaminoCi-6alkoxy, e.g. methylaminoethoxy, Cι-6dialkylaminoCι-6alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, diisopropylaminoethoxy, or dimethylaminopropoxy, hydroxyCι-6alkylamino, e.g. hydroxyethylamino or hydroxypropylamino, imido, such as phthalimido or naphthalimido, e.g. 1 ,8-naphthalimido, nitro, cyano, amidino, hydroxyl (-OH), formyl [HC(O)-], carboxyl (-CO2H), -CO2Alk5 [where Alk5 is as defined above], C1-6 alkanoyl e.g. acetyl, optionally substituted benzoyl, thiol (-SH), thioCi-βalkyl, e.g. thiomethyl or thioethyl, -SC(=NH)NH2, sulphonyl (-SO3H), Ci-6alkylsulphinyl, e.g. methylsulphinyl, ethylsulphinyl or propylsulphinyl, Ci-βalkylsulphonyl, e.g. methylsulphonyl, ethylsulphonyl or propylsulphonyl, optionally substituted Cβ-i oarylsulphonyl e.g. phenylsulphonyl, dichlorophenylsulphonyl, aminosulphonyl (-SO2NH2), Ci-βalkylaminosulphonyl, e.g. methylamino- sulphonyl or ethylaminosulphonyl, Ci -βdialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, optionally substituted phenylaminosulphonyl, carboxamido (-CONH2), Ci-6alkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, Ci-βdialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoCi-βalkylamino- carbonyl, e.g. aminoethylaminocarbonyl, C -6dialkylaminoCι-6alkylamino- carbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino, Cι_ βalkylaminoarbonylamino, e.g. methylaminocarbonylamino or ethylamino- carbonylamino, Ci-βdialkylaminocarbonylamino, e.g. dimethylamino- carbonylamino or diethylaminocarbonylamino, Cι_6alkylaminocabonylCι- βalkylamino, e.g. methylaminocarbonylmethylamino, aminothiocarbonyl- amino, Cι-6alkyl-aminothiocarbonylamino, e.g. methylaminothiocarbonyl- amino or ethylaminothiocarbonylamino, Ci-δdialkylaminothiocarbonyl- amino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonyl- amino, Ci-6alkylaminothiocarbonylCι-6alkyl-amino, e.g. ethylaminothio- carbonylmethylamino, -CONHC(=NH)NH2, Cι-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, Ci-βdialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, optionally substituted phenylsulphonylamino, aminosulphonylamino (-NHSO2NH2), Ci-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethyl- aminosulphonylamino, Ci-βdialkylaminosulphonylamino, e.g. dimethyl- amiπosulphonylamino or diethylaminosulphonylamino, optionally substituted morpholinesulphonylamino or morpholinesulphonylCi-βalkyl-amino, optionally substituted phenylaminosulphonylamino, Ci-6alkanoyl-amino, e.g. acetylamino, aminoCι -6alkanoylamino e.g. aminoacetylamino, Cι- 6dialkylaminoCι-6alkanoylamino, e.g. dimethylaminoacetylamino, Cι- 6alkanoylaminoCι-6alkyl, e.g. acetylaminomethyl, Ci-βalkanoylaminoCi- βalkylamino, e.g. acetamidoethylamino, Ci-βalkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino or optionally substituted benzyloxy, pyridylmethoxy, thiazolylmethoxy, benzyloxycarbonylamino, benzyloxycarbonylaminoCi-βalkyl e.g. benzyloxy- carbonylaminoethyl, thiobenzyl, pyridylmethylthio or thiazolylmethylthio groups.
Where desired, two R13 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a Ci-βalkylenedioxy group such as methylenedioxy or ethylenedioxy.
It will be appreciated that where two or more R13 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group represented by R3.
Nitrogen-containing six-membered heteroarylene groups represented by the group Ar2 in compounds of formula (1 ) include pyridiyl, pyrimidindiyl, pyridazindiyl, pyrazindiyl and triazindiyl groups. Each group may be attached to the remainder of the molecule through any available ring carbon atom.
The phenylene and nitrogen-containing heteroarylene groups represented by Ar2 may be optionally substituted by one or two substituents selected from the atoms or groups -L2(Alk)tL3(R4)u described herein. Where two of these atoms or groups are present they may be the same or different.
The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates. succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
In the compounds according to the invention the group Ar1 is preferably an optionally substituted phenyl or monocyclic heteroaromatic group. Particularly useful groups of this type are optionally substituted five- or six- membered heteroaromatic groups as described previously, especially five- or six-membered heteroaromatic groups containing one or two heteroatoms selected from oxygen, sulphur or nitrogen atoms. Nitrogen- containing groups are especially useful, particularly pyridyl or pyrimidinyl groups. Particularly useful substituents present on Ar1 groups include halogen atoms or alkyl, -OR5, -SR5, -NR5R6, -CO2H, -CO2CH3, NO2 or -CN groups as described above in relation to the compounds of formula (1 )- In one group of compounds of formula (1 ) for example Ra and Ra' is each a hydrogen atom, r is zero and R is a carboxylic acid (-CO2H).
A particularly useful group of compounds according to the invention has the formula (2):
wherein -W= is -CH= or -N=;
R16 and R17, which may be the same or different is each a hydrogen atom or an atom or group -L2(Alk)tL3(R4)u in which L2, Alk, t, L3, R4 and u are as defined previously;
Alka, L1 , R1 , Ar2, Ra and R are as defined for formula (1 ); and the salts, solvates, hydrates and N-oxides thereof.
-W= in compounds of formula (2) is preferably -N=.
R16 and R17 in compounds of formula (2) is each preferably as particularly described above for compounds of formula (1 ), other than a hydrogen atom. Particularly useful R16 and R17 substituents include halogen atoms, especially fluorine or chlorine atoms, or methyl, halomethyl, especially -CF3, -CHF2 or -CH2F, methoxy or halomethoxy, especially -OCF3, -OCHF2 or -OCH2F groups. Especially prefered R16 and R17 substituents are chlorine atoms.
R in the compounds of formulae (1 ) and (2) is preferably a -CO2H group.
In one preferred group of compounds of formulae (1 ) and (2) r is preferably zero and L1 is preferably -CON(R2)-. An especially useful L1 group is -CONH-. In another preferred group of compounds of formulae (1 ) and (2) r is preferably the integer 1 and Alka is preferably an aliphatic chain, particularly a Ci-6alkyl chain, most especially a -CH2- group. In this group of compounds L1 is preferably an -O- atom.
Ra in compounds of formulae (1) and (2) is preferably a hydrogen atom or an -OH group. An especially preferred Ra atom in compounds of formula (1 ) and (2) is a hydrogen atom.
The group Ar2 in compounds of formulae (1 ) and (2) is preferably an optionally substituted phenylene group. Particularly useful groups include optionally substituted 1 ,4-phenylene groups.
Particularly useful R1 groups in compounds of the invention are those wherein R1 is a -NHCOR3 or -NHR3 group.
In general in compounds of formulae (1 ) and (2) the group R3 may especially be an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group as defined herein. Particularly useful groups of this type include optionally substituted C5.7cycloaliph.atic, especially optionally substituted cyclopentyl and cyclohexyl, optionally substituted C5-7heterocycloaliphatic, especially optionally substituted pyrrolidinyl or thiazolidinyl, optionally substituted phenyl and optionally substituted C5-7heteroaromatic, especially optionally substituted pyridyl and 1 ,3,5-triazinyl groups.
Optional substituents on these groups include in particular R13 atoms or groups where R3 is an aromatic or heteroaromatic group. Particularly useful R13 atoms or groups include a halogen atom, especially fluorine or chlorine, Ci-βalkoxy, especially methoxy, optionally substituted phenoxy and phenylthio, especially phenoxy and 2,5-dimethoxyphenylthio, hydroxyCi-βalkylamino, especially hydroxyethylamino, Ci-βalkylsulphinyl especially propylsulphinyl, Ci-βalkylsulphonyl, especially propylsulphonyl or Cβ-ioarylsulphonyl, especially phenylsulphonyl or dichlorophenylsulphonyl. Where R3 is a nitrogen-containing heterocycloaliphatic group such as a pyrrolidinyl or thiazolidinyl group optional substituents include in particular -(L5)p(Alk3)qR12 groups as described earlier.
Particularly useful -(L5)p(Alk3)qR12 groups include those in which p is the integer 1 and L5 is a -CO- or -S(O)2- group. When L5 is -CO- Alk3 is preferably present (i.e. q is preferably an integer 1 ) and in particular is a -CH2-chain. R12 in groups of this type is preferably a hydrogen atom. When L5 is -S(O)2- q is preferably zero. Compounds of this type in which R1 2 is an optionally substituted aromatic or heteroaromatic group, especially an optionally substituted phenyl, e.g. dichlorophenyl, pyridyl or imidazolyl group are particularly preferred.
Particularly useful compounds of the invention include: 3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-3-({4-[2-hydroxyethyl- amino]-6-methoxy-1 ,3,5-triazin-2-yl}amine)propanoic acid;
3-[(3,5-Dichloroisonicotinoyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)- amino]phenyl}propanoic acid;
3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-3-[(2,6- dimethoxybenzoyl)amino]propanoic acid;
3-({[(4S)-3-Acetyl-1 ,3-thiazolinan-4-yl]carbonyl}amino-3-{4-[(3,5- dichloroisonicotinoyl)amino]phenyl}propanoic acid;
3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-3-[({(2S)-1-[(3,5- dichlorophenyl)sulphonyl]tetrahydro-1-H-pyrrol-2-yl}carbonyl) aminojpropanoic acid;
(2RS,3RS)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-3-{[((2S)-1-[(3,5- dichlorophenyl)sulphonyl]tetrahydro-1-H-pyrrol-2-yl)carbonyl]amino}-2- hydroxypropanoic acid;
3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-3-[({2-[(2,5- dimethoxypheπyl)thio]-3-pyridinyl}carbonyl)amino]propanoic acid; and the salts, solvates, hydrates and N-oxides thereof.
Compounds according to the invention are potent and selective inhibitors of α4 integrins. The ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter. The compounds are of use in modulating cell adhesion and in particular are of use in the prophylaxis and treatment of diseases or disorders involving inflammation in which the extravasation of leukocytes plays a role and the invention extends to such a use and to the use of the compounds for the manufacture of a medicament for treating such diseases or disorders.
Diseases or disorders of this type include inflammatory arthritis such as rheumatoid arthritis vasculitis or polydermatomyositis, multiple sclerosis, allograft rejection, diabetes, inflammatory dermatoses such as psoriasis or dermatitis, asthma and inflammatory bowel disease.
For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds for formula (1 ) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichloro- fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration. The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100ng/kg to 100mg/kg e.g. around 0.01 mg/kg to 40mg/kg body weight for oral or buccal administration, from around 10ng/kg to 50mg/kg body weight for parenteral administration and around 0.05mg to around 1000mg e.g. around 0.5mg to around 1000mg for nasal administration or administration by inhalation or insufflation.
The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process description, the symbols Ar1 , Alka, L1 , Ar2, R1 , Ra, Ra' and R when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in "Protective Groups in Organic Synthesis", John Wley and Sons, 1991]. In some instances, deprotection may be the final step in the synthesis of a compound of formula (1 ) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups. For convenience the processes described below all refer to a preparation of a compound of formula (1 ) but clearly the description applies equally to the preparation of compounds of formula (2).
Thus according to a further aspect of the invention, a compound of formula (1) in which R is a -CO2H group may be obtained by hydrolysis of an ester of formula (3):
Ar1(Alka)rL1Ar2CH(R1)CH(Ra)(Ra')CO2R9 (3)
where R9 is an alkyl group, for example a Ci-βalkyl group as described above. The hydrolysis may be performed using either an acid or a base depending on the nature of R9, for example an organic acid such as thfluoroacetic acid or an inorganic base such as lithium or potassium hydroxide optionally in an aqueous organic solvent such as an amide, e.g. a substituted amide such as dimethylformamide, an ether, e.g. a cyclic ether such as tetrahydrofuran or dioxane or an alcohol, e.g. methanol at around ambient temperature. Where desired, mixtures of such solvents may be used.
Esters of formula (3) in which R1 is a -NHCOR3 group may be prepared by coupling an amine of formula (4):
or a salt thereof with an acid R3CO2H or an active derivative thereof. Active derivatives of acids include anhydrides, esters and halides.
The coupling reaction may be performed using standard conditions for reactions of this type. Thus for example the reaction may be carried out in a solvent, for example an inert organic solvent such as an amide, e.g. a substituted amide such as dimethylformamide, an ether, e.g. a cyclic ether such as tetrahydrofuran, or a halogenated hydrocarbon, such as dichloromethane, at a low temperature, e.g. around -30°C to around ambient temperature, optionally in the presence of a base, e.g. an organic base such as an amine, e.g. triethylamine, pyridine, or dimethyl- aminopyridine, or a cyclic amine, such as N-methylmorpholine.
Where an acid R3CO2H is used, the reaction may additionally be performed in the presence of a condensing agent, for example a diimide such as 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,N'-dicyclo- hexylcarbodiimide, advantageously in the presence of a catalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as 1 -hydroxy- benzotriazole. Alternatively, the acid may be reacted with a chloroformate, for example ethylchloroformate, prior to reaction with the amine of formula (4).
Similar reaction conditions and reagents may be used to generate an intermediate ester of formula (3) in which R1 is a -CONHR3 group, from an amine R3NH2 or a salt thereof, and an acid Ar1 (Alka)rL1Ar2CH(CO2H)C(Ra)(Ra')CO2R9 or an active derivative thereof. Equally, similar reaction conditions and reagents may be used to obtain an ester of formula (3) in which R1 is a -NHC(O)OR3 group from an amine of formula (4) and an appropriate chloroformate CICO2R3.
Esters of formula (3) in which R1 is a -NHCSR3 or -CSNHR3 group may be prepared by treating a corresponding ester in which R1 is a -NHCOR3 or -CONHR3 group with a thiation reagent, such as Lawesson's Reagent, in an anhydrous solvent, for example a cyclic ether such as tetrahydrofuran, at an elevated temperature such as the reflux temperature.
This reaction may not be particularly suitable with starting materials in which other carbonyl groups are present, for example in Ar1, Ar2 and/or R3, and which might undesirably participate in the reaction. To avoid this the reaction with the thiation reagent may be performed earlier in the synthesis of the compound of the invention with an intermediate in which other carbonyl groups are absent and any required carbonyl groups then subsequently introduced by for example acylation as generally described hereinafter.
Intermediate esters of formula (3) in which R1 is a -NHCONHR3 or -NHCSNHR3 group may be prepared from the corresponding amine of formula (4) by reaction with an isocyanate R3NCO or isothiocyanate R3NCS. The reaction may be performed in a solvent such as acetonitrile or an ether at an elevated temperature, e.g. the reflux temperature.
Amines of formula (4) may also be used to obtain intermediate esters of formula (3) in which R1 is a -NHSO2R3 group by reaction with a reagent R3SO2L6 (where L6 is a leaving group such as a halogen atom, e.g. a bromine, iodine or chlorine atom) in the presence of a base, for example an inorganic base such as sodium hydride, in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide, at for example ambient temperature.
Intermediate esters of formula (3) in which R1 is a -NHR3 group may be prepared by coupling an amine of formula (4) with a reagent R3X2 in which X2 is a leaving atom or group such as a halogen atom, e.g. a fluorine, bromine, iodine or chlorine atom or a sulphonyloxy group such as an alkylsulphonyloxy, e.g. trifluoromethylsulphonyloxy or arylsulphonyloxy, e.g. p-toluenesulphonyloxy group.
The coupling reaction may be carried out using standard conditions for reactions of this type. Thus for example the reaction may be carried out in a solvent, for example an alcohol, e.g. methanol or ethanol, at a temperature from around ambient to the reflux temperature, optionally in the presence of a base such as an amine, e.g. triethylamine or N,N- diisopropylethylamine, or a cyclic amine, such as N-methylmorphholine or pyridine.
The intermediate amines of formula (4) may also be used to obtain esters of formula (3) in which R1 is a -NHSO2NHR3 group by reaction with a sulphamide R3NHSO2NH2 in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
In a further example compounds of the invention may be obtained from resin linked (e.g. Wang resin) amino acids e.g. suitably N-protected e.g. fluorenylmethoxycarbonyl protected aryl amino acids. Resin linked amines of formula (4) (R9 represents the resin linker) may be obtained for example by reduction of the nitro [-NO2] group of suitable resin linked amino acids e.g. nitroaryl amino acids with for example a tin reagent e.g. stannous chloride in a solvent such as an amide e.g. a substituted amide such as dimethylformamide at for example ambient temperature, followed by reaction of the newly generated amino (-NH2) group with for example an acid chloride Ar1 (Alka)rCOCI or an isocyanate Ar1 (Alka)rNCO optionally in the presence of an organic base e.g. an amine such as diisopropylethyl- amine is a solvent such as a halogenated hydrocarbon e.g. dichloro- methane, at for example ambient temperature, followed by N-deprotection with for example an organic amine e.g. piperidine in a solvent such as an amide e.g. a substituted amide such as dimethylformamide. Resin linked componds of formula (3) may be obtained by reaction of resin linked compounds of formula (4) with for example an acid (R3CO2H), isocyanate (R3NCO), isothiocyanate (R3NCS), sulphonyl halide (R3SU2L6) or halide (R3X) as previously described for the preparation of esters of formula (3). Compounds of the invention may be obtained from resin-linked compounds of formula (3) by cleavage from the resin with for example an organic acid, e.g. trifluoroacetic acid in an organic solvent, for example a halogenated hydrocarbon e.g. dichloromethane.
The amines of formula (4) may be obtained from simpler, known compounds by one or more standard synthetic methods employing substitution, oxidation, reduction or cleavage reactions as described below and in the Examples hereinafter. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures, including for example those just described to obtain esters of formula (3). It will be appreciated that these methods may also be used to obtain or modify other compounds of formulae (1) and (2) where appropriate functional groups exist in these compounds. Additionally, although a number of the R3 containing intermediates and the acid Ar1(Alka)rL1Ar2CH(CO2H)C(Ra)(Ra')CO2R9 for use in the coupling reactions described above are known, others can be derived therefrom using these standard synthetic methods.
Thus compounds of the invention and intermediates thereto may be prepared by alkylation, arylation or heteroarylation. For example, compounds containing a -L2H, or -L3H group (where L2 and L3 is each a linker atom or group) may be treated with reagent (R4)uL3Alk3X2 or R4aX2 respectively in which X2 is as previously described and R a is an alkyl group.
The reaction may be carried out in the presence of a base such as a carbonate, e.g. cesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydro-furan.
In another example, compounds containing a -L2H or -L3H group as defined above may be functionalised by acylation or thioacylation, for example by reaction with one of the alkylating agents just described but in which X2 is replaced by a -C(O)X3, C(S)X3, -N(R5)COX3 or -N(R5)C(S)X3 group in which X3 is a leaving atom or group as described for X2. The reaction may be performed in the presence of a base, such as a hydride, e.g. sodium hydride or an amine, e.g. triethylamine or N-methyl- morpholine, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane or carbon tetrachloride or an amide, e.g. dimethylformamide, at for example ambient temperature. Alternatively, the acylation or thioacylation may be carried out under the same conditions with an acid or thioacid (for example one of the alkylating agents described above in which X2 is replaced by a -CO2H or -COSH group) in the presence of a condensing agent, for example a diimide such as 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide or N,N'-dicyclohexylcarbodi- imide, advantageously in the presence of a catalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as 1 -hydroxybenzotriazole. Alternatively the acid may be reacted with a chloroformate, for example ethylchloroformate, prior to the desired acylation reaction
In a further example compounds may be obtained by sulphonylation of a compound containing an -OH group by reaction with one of the above alkylating agents but in which X2 is replaced by a -S(O)Hal or -SO2Hal group in which Hal is a halogen atom such as chlorine atom] in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature.
In another example, compounds containing a -L2H or -L3H group as defined above may be coupled with one of the alkylation agents just described but in which X2 is replaced by an -OH group in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl, diisopropyl- or dimethylazodicarboxylate.
In a further example, ester groups -CO2R5 or -CO2Alk1 in the compounds may be converted to the corresponding acid [-CO2H] by acid- or base- catalysed hydrolysis depending on the nature of the groups R5 or Alk1. Acid- or base-catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
In a further example, -OR5 or -OR14 groups [where R5 or R14 each represents an alkyl group such as methyl group] in compounds of formula (1 ) may be cleaved to the corresponding alcohol -OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around -78°C.
Alcohol [-OH] groups may also be obtained by hydrogenation of a corresponding -OCH2R14 group (where R14 is an aryl group) using a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethanol in the presence of ammonium formate, cyclohexadiene or hydrogen, from around ambient to the reflux temperature. In another example, -OH groups may be generated from the corresponding ester [-CO2Alk1 or CO2R5] or aldehyde [-CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
In another example, alcohol -OH groups in the compounds may be converted to a corresponding -OR5 group by coupling with a reagent R5OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
Aminosulphonylamino [-NHSO2NH23 groups in the compounds may be obtained, in another example, by reaction of a corresponding amine [-NH2] with sulphamide in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
In a further example amine (-NH2) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
In a further example, amine [-NH2] groups in compounds of formula (1 ) may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
In another example, a nitro [-NO2] group may be reduced to an amine [- NH2], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around -78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group may be introduced by using dimethylformamide as the electrophile; a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile.
In another example, sulphur atoms in the compounds, for example when present in a linker group L2 or L3 may be oxidised to the corresponding sulphoxide or sulphone using an oxic. ing agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature.
N-oxides of compounds of formula (1 ) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70°C to 80°C, or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
Salts of compounds of formula (1 ) may be prepared by reaction of a compound of formula (1 ) with an appropriate base in a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol using conventional procedures.
Where it is desired to obtain a particular enantiomer of a compound of formula (1 ) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.
Thus for example diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (1) e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
In another resolution process a racemate of formula (1 ) may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
Chromatography, recrystalliation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention. The following Examples illustrate the invention. All temperatures are in °C. The following abbreviations are used:
NMM - N-methylmorpholine; EtOAc - ethyl acetate;
BOC - butoxycarbonyl; Ar - aryl;
Me - methyl; THF - tetrahydrofuran;
DMSO - dimethylsulphoxide; app - apparent tBu - tertiary butyl; HOBT - 1 -hydroxybenzotriazole
DIEA - Diisopropylethylamine; MeOH - methanol
EDC - 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; EtOH - ethanol; DMF: - dimethylformamide;
DCM: - dichloromethane; TFA - trifluoroacetic acid
All NMR's were obtained at 300MHz.
INTERMEDIATE 1
3-Amino-3-rø-nitrophenvl )ropanoic acid
To a hot solution of sodium ethoxide prepared from sodium (9.33g, 405mmol) and EtOH (330ml) was added a hot solution of hydroxylamine hydrochloride (28.17g, 405mmol) in water (18ml). A white precipitate was formed immediately. The mixture was cooled rapidly and the solid removed by filtration and washed with EtOH (40ml). The filtrate was then returned to the reaction flask and 4-nitrocinnamic acid (30g, 155mmol) was added. The mixture was heated to reflux overnight. The resulting mixture was cooled to 0° and the precipitate filtered off and the solid washed with EtOH (50ml), water (50ml) and finally EtOH (50ml) to give the title compound as a pale yellow solid (16g, 49%). δH (D2O) 8.31 (2H, d, J 8.7Hz, ArH), 7.69 (2H, d, 8.7Hz, ArH), 4.81 (1 H, app. dd. 7.2, 7.1 CHNH2), 2.94 (1 H, dd, J 16.4, 7.7Hz, CHAHB) and 2.86 (1 H, dd, J 16.4 and 6.7Hz, CHAHB); mZ (ES+, 60V) 211 (MH+).
INTERMEDIATE 2 Methvl-3-amino-3-f4-nitrophenvnpropanoate
Intermediate 1 (5g, 23.8mmol) was added to a solution of acetyl chloride
(5ml) in MeOH (125ml). The resulting solution was stirred at room temperature overnight. The solvents were then removed in vacuo and the resulting solid was triturated with hot ether, collected by filtration and washed with more ether to leave the title compound as a pale yellow powder (5.35g, 100%). δH (D2O) 8.32 (2H, d, J 8.9Hz, ArH), 8.75 (2H, d, J
8.9Hz, ArH), 4.90 (1 H, dd, 7.2, 6.9Hz, CHNH2), 3.70 (3H, s, CO2Me), 3.19 (1 H, dd, 17.1 , 7.5 Hz, CHAHB) and 3.09 (1 H, dd, J 17.1 , 6.6Hz, CHAMB); m/z (ES+, 60V) 225 (MH+).
INTERMEDIATE 3 Methyl-3-ft-butvloxvcarbonvlamino^-3-f4-nitrophenvnpropanoate
A solution of di-fett-butyl dicarbonate (6.58ml, 28.6mmol) in THF (50ml) was added dropwise to a stirred soution of Intermediate 2 (5.35g,
23.8mmol) and sodium hydrogen carbonate (4.19g, 49.9mmol) in THF
(100ml) and water (100ml). The mixture was stirred overnight at room temperature. The THF was then removed in vacuo and the aqueous residue extracted with EtOAc (75ml x 3). The combined organics were then washed with 10% aqueous citric acid (100ml) and brine (100ml), dried
(Na2SO4) and evaporated under reduced pressure. The oil obtained was taken up in hot ether. The solution was then cooled to yield a white precipitate which was collected by filtration and washed with hexane to give the title compound (6.69g, 87%). δH (CDCI3) 8.20 (2H, d, J 8.7Hz, ArH), 7.47 (2H, d, J 8.7Hz, ArH), 5.71 (1 H, br s, NH), 5.17 (1 H, app. br s, CHNH),
3.63 (3H, s, CO2Me), 2.87 (2H, app. br d J 5.6Hz, CH2) and 1.42 (9H, s,
*Bu); m/z (ES+, 60V) 347 (M ++ Na).
INTERMEDIATE 4 Methvl-3-(4-aminoDhenvn-3-ft-butvloxvcarbonvlamino propanoate
A solution of Intermediate 3 (5.6g, 17.3mmol) and tin (II) chloride dihydrate (19.6g, 86.5mmol) in EtOH (100ml) was stirred overnight at room temperature. The EtOH was then removed in vacuo and the residue partitioned between DCM (250ml) and saturated aqueous NaHCO3 (100ml). The resulting solid precipitate was removed by filtration and washed with copious DCM. The filtrate was then separated and the aqueous extracted with DCM(3 x 100ml). The combined organics were finally washed with brine (150ml), dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography (Siθ2; DCM/EtOAc, 4:1 ) gave the title compound as a yellow oil (3.77g, 74%) δH (DMSO-d6) 7.20 (1 H, br d, J 8.5Hz, CONH), 6.93 (2H, d, J 8.4Hz, ArH), 6.47 (2H, d, A 8.4Hz, ArH), 5.00 (2H, br s, NH2), 4.74 (1 H, m, ArCH), 3.52 (3H, s, CO2Me), 2.67 (1 H, dd, J 15.1 , 8.4Hz, CHAHBCO2Me), 2.56 (1 H, dd, J 15.1 , 6.8Hz, CHAHBCO2Me) and 1.33 (9H, s, ffiu). m/z (ES+, 60V) 295 (MH+).
INTERMEDIATE $ Mgt yl-3-(tgr -b ylQxycg QnylaminQ)-3-{4-[(3,$- dichloroisonicotinovnaminolphenvβpropanoate
To a solution of Intermediate 4 (3.77g, 12.8mmol) in DCM (50ml) was added NMM (1.55ml, 14.1 mmol) and a solution of 3,5-dichloroisonicotinyl chloride (prepared by the methods detailed in International Patent
Application WO99/35163) (2.97g, 14.1mmol) in DCM (2ml). The reaction mixture was stirred for 3h and then diluted with DCM (200ml) and washed with water (2 x 75ml) and brine (75ml), dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography (Siθ2; DCM /EtOAc, 4:1 ) gave the title compound as a white solid (4.7g, 81 %). δH (CDCI3) 8.93 (1 H, br s, NH), 8.51 (2H, s,
ArCl2JH), 7.33 (2H, d, A 8.3Hz, ArH), 7.13 (2H, d, A 8.3Hz, ArH), 5.75 (1 H, br s, NJHBoc), 4.90 (1 H, app. dd, 14.2, 6.0Hz, CHNH), 3.61 (3H, s, CO2Me), 2.75 (2H, d, A 6.0Hz, CH2) and 1.35 (9H, s *Bu); m/z (ES+, 60V)
490 (M++ Na).
INTERMEDIATE S
Methvl-3-amino-3-M-rr3.5-dichloroisonicotinovnaminolphenvl> propanoate trifluoroacetic acid salt
To a solution of Intermediate 5 (4.7g, 10.3mmol) in DCM (100ml) and water (0.5ml) was added TFA (1.59ml, 20.6mmol) dropwise. The solution was stirred at room temperature for 4h. The volatiles were then removed in vacuo and the resulting yellow oil triturated with hexane/ether (~1 :2) to give a sticky semi-solid. A small amount of EtOAc was then added and the solution heated to produce a white solid. The solution was then cooled, filtered and the solid washed with ether to leave the title compound (4.9g, 100%) as a white solid. δH (D20) 8.69 (2H, s, ArCI2H), 7.72 (2H, d, J 8.4Hz, ArH), 7.59 (2H, d, A 8.4Hz, ArH), 4.91 (1 H, dd, A 7.2, 7.2Hz, CH), 3.75 (3H, s, CO2Me), 3.30 (1 H, dd, A 16.9, 7.5Hz, CHAHB) and 3.21 (1 H, dd, 16.9, 7.0Hz, CHAHB); m/z (ES+, 60V) 368 (MH+). INTERMEDIATE 7 Λ 3.5-Dichlorobenzenesulphonvn- -proline methvl ester
3,5-Dichlorobenzenesulphonyl chloride (5.0g, 20.36mmol) was added portionwise over 30min to a solution of -proline methyl ester hydrochloride (3.69g, 22.4mmol) and DIEA (7.8ml, 44.8mmol) in DCM (100ml) at 0°. The reaction mixture was stirred overnight at room temperature then concentrated in vacuo. The residue was dissolved in EtOAc (100ml) and washed with saturated aqueous NaHCO3 (100ml), citric acid (10%, 100ml) and saturated aqueous NaHCO3 (100ml). The organic phase was dried (MgSO4) and concentrated in vacuo. Column chromatography (Siθ2, EtOAc/hexane, 80:20) gave the title compound (3.77g). δH (CDCI3) 7.8 (2H, d, J 2.0Hz, ArH), 7.5 (1 H, d, J 2.0Hz, ArH), 4.4 (1 H, m, CHα), 3.7 (3H, s, CO2Me), 3.4 (2H, m, CH2N), 2.0 (4H, m, NCH2CH2CH2); /z (ES+, 70V), 338 (MH+).
INTERMEDIATE S Λ/-f3.5-Dichlorobenzeπesulphonvn- -proline
Lithium hydroxide monohydrate (555mg, 13.24mmol) was added to Intermediate 7 (3.73g, 11.03mmol) in THF (25ml) and water (25ml). The mixture was stirred at room temperature overnight then concentrated in vacuo. Water was added to the residue and the pH adjusted to pH1 with 1.0M HCI. The resulting precipitate was filtered off, washed with water and dried to give the title compound as a white solid (3.48g). δH (CDCI3) 7.8 (2H, s, ArH), 7.6 (1H, s, ArH), 4.4 (1 H, m, CHα), 3.6 (1H, m, NCHAHB), 3.5 (1 H, m, NCHAHB), 2.0 (4H, m, NCH2CH2CH2); m/z (ES+, 70V) 324 (MH+).
INTERMEDIATE 9
Ethvl 12RS. 3 ?S)-3-azido-2-hvdroxv-3-f4-nitrophenvnDropanoat.a A mixture of ethyl (2RS, 3RS)-3-(4-nitrophenyl-2-oxirane carboxylate [prepared by the method of Moyna, G., Williams, H. J., Scott, A. I., Synth. Commun, (1996) £6, 2235-9] (2.5g, 10.5mmol) sodium azide (3.4g, 52.5mmol), ethyl formate (10ml) in EtOH/water (8:1 , 50ml) was heated at 50° overnight. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4) and evaporated in vacuo. Column chromatography (SiO2J MeOH/DCM, 1:99) gave the title compound as a yellow oil (2.34g) (less polar regioisomer). δH (CDCI3) 8.24 (2H, d, A 8.8Hz, ArH), 7.55 (2H, d, A 8.9Hz, ArH), 5.02 (1 H, d, J 3.7Hz, CHN3), 4.57 (1 H, dd, A 5.3, 3.7Hz, CHOH), 4.25-4.14 (2H, m, CO2CH2), 3.15 (1 H, d, A 5.5Hz, OH), 1.21 (3H, t, 7.2Hz, CO2CH2CH3)- m/z (ES+, 70V) 253 (M+- N2).
INTERMEDIATE 10 Ethyl (2RS. 3ffS)-3-amino-3-(4-aminophenyl)-2-hvdroxypropanoate
A mixture of Intermediate 9 (1.38g, 4.93mmol) and palladium on charcoal (10%wt, Pd, 140mg) in EtOH (50ml) was stirred under a hydrogen atmosphere (balloon) at room temperature overnight. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound as a yellow gum (1.1 Og) δH (DMSO-d6) 6.93 (2H, d, A 8.4Hz, ArH), 6.44 (2H, d, A 8.4Hz, ArH), 4.00 (2H, q, A 7.1 Hz, CO2CH2CH3), 4.00 (1 H, CHNH2), 3.82 (1 H, d, J 6.0Hz, CHOH), 1.12 (3H, t, J 7.1 Hz, CO2CH2CH3), 4.80 (2H, br s, ArNH2), 3.30 (2H, v br s, CHNH2), 1.90 (1 H, v br s, OH); m/z (ES+, 70V) 208 (M+-NH3).
INTERMEDIATE 11 3- 9-Fluorenylmethoxycarbonylamino)-3-(4-nitrophenyl)propanoic acid.
A cold (0°) solution of 3-amino-3-(4-nitrophenyl)propanoic acid (3.2g, 15mmol) in 10% aqueous sodium carbonate (60ml) and 1 ,4-dioxan (30ml) was treated portion-wise with 9-fluorenylmethoxycarbonyl-N- hydroxysuccinimide (5.6g, 17mmol) in 1 ,4-dioxan (15ml) and the mixture stirred at room temperature for 12h. The mixture was poured into water (300ml) and the aqueous phase washed 3 times with ether. The aqueous layer was then acidified with solid citric acid and extracted into ether. The combined organic layers were dried (MgSO4) and evaporated to a yellow oil then triturated from hexane and EtOAc to afford the title compound as a yellow solid (2.83g); m/z (ES+, 70V) 432 (MH+).
INTERMEDIATE 12
Resin bound 3-(9-Fluorenylmethoxycarbonylamino)-3-(4- aminophenvDpropanoic acid Wang resin (Advanced Chemtech, 2.5g, O.8mmol/g, 2mmol equivalent) in a mixture of DMF (20ml) and DCM (20ml) was treated with 3-(9- fluorenylmethoxycarbonylamino)-3-(4-nitrophenyl)propanoic acid (2.6g, 6mmol), 4-dimethylaminopyridine (244mg, 2mmol) and 1 ,3-diisopropyl- carbodiimide (940μl, 6mmol) and the mixture agitated under nitrogen at room temperature for 24h. The resin was filtered and washed with DMF and DCM. The resin was treated with a 1 M solution of stannous chloride dihydrate in DMF (50ml) at room temperature for 8h then washed as before to give the title compound.
INTERMEDIATE 13
Resin bound 3-f4-rf3.5-dichloroisonicotinovnaminolphenyl}-3- a.mipoprQpa.nQiP acjd.
Intermediate 12 (3.3g, 0.28mmol/g, 0.9mmol equivalent) was treated with DIEA (1.6ml, 9mmol) and 3,5-dichloro-4-pyridinecarbonyl chloride (1.9g, 9mmol) in DCM (20ml) with agitation at room temperature for 12h. The resin was filtered and washed with DMF and DCM followed by treatment with a 20% solution of piperidine in DMF (40ml) for 40min at room temperature then filtered and washed as before to afford the tjtie compound.
INTERMEDIATE 14
Resin bound 3 4-H2.6-dichlorobenzovnaminolphenvlV3- aminpprppa.npic acid. Intermediate 14 was prepared in a similar manner to Intermediate 13 from Intermediate 12, using 2,6-dichlorobenzoylchloride for 8h.
EXAMPLE 1
Methvl-3-r-f2-chloronicotinovhamino1-3-{4-[(3.5- dichloroisonicotinvnaminolphenylϊpropanaote
To a suspension of Intermediate 6 (600mg, 1.24mmol) in DCM (25ml) was added 2-chloroπicotinic acid (195mg, 1.24mmol), NMM (287μl, 2.61 mmol), HOBT (190mg, 1.37mmol) and EDC (267mg, 1.37mmol). The resulting solution was stirred overnight at room temperature and then diluted with DCM (100ml) and washed with saturated aqueous NaHCO3 (50ml), water (50ml) and brine (50ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was then purified by column chromatography (Siθ2, DCM/MeOH, 95:5) to give the title compound as a creamy solid. δH (DMSO-d6) 9.18 (1H, d, A 8.4Hz, NH), 8.79 (2H, s, ArCI2H), 8.46 (1 H, dd, A 4.8, 1.8Hz, ArCIH), 7.82 (1 H, dd, A 7.5, 1.8Hz, ArCIH), 7.62 (2H, d, A 8.5Hz, ArH), 7.49 (1 H, dd, A 7.5, 4.8Hz, ArCIH), 7.41 (2H, d, A 8.5Hz, ArH), 5.45- 5.37 (1 H, m, CH), 3.60 (3H, s, OMe) and 2.86 (2H, d, A 8.0Hz, CH2); m/z (ES+, 60V) 507 (MH+).
EXAMPLE 2 3-r(2-Chloronicotinovltømino1-3 4-r(3.5-dichloroisonicotinoyl)- aminolphenvltoropanoic acid
The compound of Example 1 (340g, 0.67mmol) was dissolved in a mixture of THF (5ml) and water (5ml). Lithium hydroxide monohydrate (31 mg, 0.74mmol) was added and the mixture stirred at room temperature for 3h. The THF was removed under reduced pressure and the aqueous residue acidified with aqueous HCI (1 M). The resulting white precipitate was collected by filtration and washed well with water. Freeze drying from a mixture of MeOH and water gave the title compound as a white solid (193mg, 58%). δH (DMSO-d6) 12.30 (1 H, br s CO2H), 10.91 (1 H, s, NH), 9.12 (1 H, d, A 8.2Hz, NH), 8.79 (1 H, s, ArCI2H), 8.46 (1 H, dd, A 4.8, 1.9Hz, ArCIH), 7.81 (1 H, dd, A 7.5, 1.9Hz, ArCIH), 7.61 (2H, d, A 8.5Hz, ArH), 7.49 (1 H, dd, A 7.5, 4.8Hz, ArCIH), 7.41 (2H, d, A 8.5Hz, ArH), 5.38-5.31 (1 H, m, CH) and 2.84-2.69 (2H, m, CH2); m/z (ES+, 60V) 493 (MH+).
EXAMPLE 3
Methvl-3-(3.5-dichloroisonicotinovlamino -3-{4-r(3.5- dichloroisonicotinovnaminolphenvltoropanoate
To a suspension of Intermediate 6 (600mg, 1.24mmol) in DCM (25ml) was added NMM (287μl, 2.61 mmol) followed by 3,5-dichloroisonicotinoyl chloride (272mg, 1.36mmol). The mixture was stirred for 2h and then diluted with DCM (100ml) and washed with water (2 x 50ml) and brine (50ml), dried (Na2SO4) and evaporated under reduced pressure. The residual peach foam was purified by column chromatography (Siθ2, DCM/ MeOH, 92:8) to give the title compound as a pale cream oil (629mg, 94%). δH (CDCI3) 9.01 (1 H, s, NH), 8.41 (2H, s, ArCI2H), 8.39 (2H, s, ArCI2H), 7.73 (1 H, d, A 8.2Hz, NH), 7.44 (2H, d, A 8.5Hz, ArH),7.28 (2H, d, A 8.5Hz, ArH), 5.49 (1 H, dd, A 8.0, 6.4Hz, CH), 3.62 (3H, s, Me), 2.94 (1 H, dd, A 16.1 , 6.6Hz, CHAHB) and 2.86 (1 H, dd, J 16.1 , 6.2Hz, CHAHB); m/z (ES+ 60V) 241 (MH+).
EXAMPLE 4
3-rf3.5-Dichloroisonicotinovhamino1-3-f4-r-.3.5- dichloroisonicotinovnamino1phenvl propanoic acid
The title compound was prepared by the method of Example 2 from the compound of Example 3 as a pale cream solid (356mg, 58 %). δH (DMSO d6) 10.92 (1 H, s, NH), 9.41 (1 H, d, A 8.1 Hz, NH), 8.78 (2H, s, ArCI2H), 8.68 (2H, s, ArH), 5.37 (1 H, app. q. A 7.4Hz, CH) and 2.75 (2H, d, A 7.4Hz, CH2); m/z. (ES+, 60V) 527 (MH+).
EXAMPLE 5 Methvl-3-f4-r..3.5-dichloroisonicontinovnamino1phenvlV3-r(2.6- dimethoxvbenzovnaminolpropanoate
To a suspension of Intermediate 6 (600mg, 1.24mmol) in DCM (25ml) was added NMM (287ml, 2.61 mmol) and 2,6-dimethoxybenzoyl chloride (23mg,1.36mmol). The reaction mixture was stirred for a further 2h and then diluted with DCM (100ml) and washed with water (2 x 100ml) and brine (1 x 100ml), dried (Na2SO4) and evaporated under reduced pressure. The resulting semi-solid was purified by column chromatography (Siθ2, DCM /MeOH, 92:8) to give the title compound as a pale cream oil (658mg, 100%). δH (CDCI3) 8.48 (2H, s, ArCI2H), 8.38 (1 H, s, NH), 7.55 (2H, d, J 8.6Hz, ArH), 7.39 (2H, d, A 8.6Hz, ArH), 7.28 (1 H, t, A 8.4Hz, Ar(OMe)2H), 6.91 (1 H, d, A 8.6Hz, NH), 6.55 (2H, d, A 8.4Hz, Ar(OMe)2H), 5.60-5.30 (1 H, m, CH), 3.78 (6H, s, OMe x 2), 3.63 (3H, s, CO2Me), 3.01 (1 H, dd, A 16.0, 5.7Hz, CHAHB) and 2.93 (1 H, dd, J 16.0, 5.7Hz, CHAHB); m/z (ES+, 60V) 532 (MH+).
EXAMPLE 6
3-{4-r(3.$-DichlprQi?onicotinoyl)aminQ]ph nyl}-3-[(2.6- dimethoxvbenzovnaminolpropanoic acid
The title compound was prepared by the method of Example 2 from the compound of Example 5 as a white solid (270mg, 42%). δH (DMSO-d6)
10.84 (1 H, s, NH), 8.77 (2H, s, ArCI2H), 8.50-8.40 (1 H, m, NH), 7.58 (2H, d, A 8.5Hz, ArH), 7.40 (2H, d, A 8.5Hz, ArH), 7.27 (1 H, t, A 8.4Hz, Ar(OMe)2H), 6.64 (2H, d, A 8.4Hz, Ar(OMe)2H), 5.30 (1 H, app. q, A 7.5Hz, CH), 3.10 (6H, s, OMe), 2.72 (1 H, dd, A 15.4, 7.0Hz, CHAHB) and 2.65 (1 H, dd, A 15.4, 7.2 CHAHB); m/z (ES+,60V) 518 (MH+).
EXAMPLE 7 Methvl-3-f4-r(dichloroisonicotinovnaminolphenvβ-3 4.6-dimethoxv-
1,3,$-triaz-2-ylaminp)prppanpate
Intermediate 6 (1.0g, 2.07mmol) was partitioned between EtOAc (100ml) and saturated aqueous NaHCO3 solution (100ml). The phases were thoroughly shaken and then separated and the aqueous layer extracted with EtOAc (2 x 100ml). The combined organic phases were dried (Na2SO4) and evaporated to leave the free amine. A solution of the amine (626mg, 1.70mmol) 2-chloro-4,6-dimethoxy-1 ,3,5-triazene (404mg, 2.30mmol) and NMM (233μl, 2.30mmol) in MeOH was stirred overnight at 60°. The MeOH was removed in vacuo and the residue partitioned between EtOAc (100ml) and saturated aqueous NaHCU3 (100ml). The phases were separated and the aqueous layer extracted with EtOAc (2 x 75ml). The combined organics were then washed with 5% aqueous citric acid (50ml), saturated aqueous NaHCO3 (50ml) and brine (50ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography (S1O2, DCM/MeOH, 92:8) to give the title compound as a cream foam (370mg, 43%) δH (CDCI3) 9.29 (H, s, NH), 8.38 (2H, s, ArCI2H), 7.54 (2H, d, A 8.5Hz, ArH), 7.28 (2H, d, J 8.5Hz, ArH), 6.81 (1 H, d, A 8.4Hz, NH), 5.53 (1 H, dd, A 6.7, 6.2Hz, CH), 3.85 (3H, s, OMe), 3.83 (3H, s, OMe), 3.59 (3H, s, CO2Me), 2.96 (1 H, dd, A 16.8, 6.7Hz, CHAHB) and 2.84 (1 H, dd, A 16.8, 6.2Hz, CHAHB); m z (ES+, 60V) 529 (M++ Na).
EXAMPLE 9
3-{4-r(3.5-Dichloroisonicotinovnamino1phenvlV3-f4.6-dimethoxv-1.3.5- triaz-2-vlaminoipropanoic acid
The title compound was prepared by the method of Example 2 from the compound of Example 7 as a white powder (170mg, 47%). δH (DMSO- d6) 10.89 (1 H, s, NH), 8.48 (2H, s, ArCI2H), 8.49 (1 H, d A 8.3Hz, NH), 7.58
(2H, d, A 8.5Hz, ArH), 7.40 (2H, d, A 8.5Hz, ArH), 5.36 (1 H, ddd, J 8.6, 8.3, 6.4Hz, CH), 3.80 (6H, s, OMe), 2.87 (1 H, dd, A 15.9, 8.6Hz, CHAHB) and 2.70 (1 H, dd, A 15.9, 6.0Hz, CHAHB); m/z (ES+, 60V) 493. (MH+).
EXAMPLE 9 Methvl 3-{4-r(3.5-dichloroisonicotinovnaminolphenvlV3-(r6- fprppyl?ulphpnyl)-4-pyrimip:}nyl]aminp}prppanpate
A mixture of Intermediate 6 (502mg, LOOmmol) 4,6-bis(propylsulphonyl) pyrimidine (prepared from 4,6-dichloropyrimidine, propanethiol and sodium hydride in THF) (321 mg, 1.10mmol) and DIEA (348μl, 2.00mmol) in acetonitrile (3ml) was heated at 50° overnight. The mixture was diluted with DCM, washed wth dilute HCI, dried (Na2SO4) and evaporated in vacuo. Column chromatography (Siθ2- MeOH/DCM, 6:94) gave the title compound as a white foam (344mα). δH (DMSO-d6) 10.91 (1 H, s, CONH), 8.77 (2H, s, CI2PyH), 8.70 (1 H, d, A 7.9Hz, NH), 8.57 (1H, s, ArH), 7.61 (2H, d, A 8.6Hz, ArH), 7.40 (2H, d, A 8.5Hz, ArH), 7.12 (1H, s.ArH), 5.55 (1 H, m, CHNH), 3.56 (3H, s, CO2Me), 3.36-3.32 (2H, m, SO2CH2), 2.93-2.89 (2H, m, CH2CO2), 1.63-1.55 (2H, m, SO2CH2CH2CH3), 0.93 (3H, t, A 7.4Hz, SO2CH2CH2CH3); m/z (ES+, 70V) 552 (MH+).
EXAMPLE 10
3-{4-r(3.5-Dichloroisonicotinovnamino1phenvlV3-frβ-
(prppyl?Mlphpnyl)-4-pyrimip:inyl3aminp}prppanpip api<>j
The title compound was prepared by the method of Example 2 from the compound of Example 9 as a white powder. δH (DMSO-d6) 12.34 (1 H, br s, CO2H), 10.90 (1 H, s, CONH), 8.77 (2H, s, CI2PyH), 8.70 (1H, d, A 7.9Hz,
NH), 8.55 (1H, s, ArH), 7.60 (2H, d, A 8.5Hz, ArH), 7.39 (2H, d, A 8.5Hz,
ArH), 7.12 (1H, s, ArH), 5.52 (1 H, m, CHNH), 3.4 (2H, m, SO2CH2), 2.90-
2.75(2H„ m, CH2CO2), 1.63-1.55 (2H, m, SO2CH2CH2), 0.93 (3H, t, A
7.4Hz, SO2CH2CH2CH3); m/z (ES+,70V) 538 (MH+).
EXAMPLE 11
Meth l S-^-chloro-e-methoxv-I.S.β-triazin-Σ- naminol-S^-^S.S- dichloroisonicotinovnaminolphenvlϊpropanoate
A solution of dichloromethoxy-1 ,3,5-triazine (396mg, 2.2mmol) in acetonitrile (5ml) was added to a mixture of Intermediate 6 (1.004g, 2mmol) and diisopropylethylamine (732μl, 4.2mmol) in acetonitrile (5ml) at 0°. After 30min the mixture was diluted with DCM, washed with dilute HCI, dried (Na2SO4) and evaporated in vacuo. Column chromatography (Siθ2- EtOAc/hexane, 65:35) gave the title compound as a colourless gum (694mg). δH (DMSO-d6, 300K) (2 rotameric species observed) 10.91 (1 H, s, CONH), 9.16 (d, A 8.1 Hz) and 9.08 (d, A 8.6Hz) together (1 H, CHNH), 8.78 (2H, s, PyH), 7.60 (2H, d, A 8.6Hz, ArH), 7.40-7.37 (2H, m, ArH), 5.41-5.32 (1H, m, CHCH2), 3.86 (3H, s, OMe), 3.56 (3H, s, OMe), 2.97 (1 H, dd, A 16.1 , 8.6Hz, CHAHBCO2), 2.87 (1 H, m, CHAHBCO2); m/z (ES+, 70V) 511 (MH+).
EXAMPLE 12
Methvl 3-f4-rf3.5-dichloroisonicotinovnaminolPhenvlV3-^4-f2- hvdroxvethvlamino1-6-methoxv-1.3.5-triazin-2-vl)amino)propanoate
A mixture of the compound of Example 11 (350mg, 0.683mmol). DIEA (119μl, 0.683mmol) and ethanolamine (4.5μl, 0.75mmol) in THF (10ml) was stirred at room temperature overnight. The mixture was diluted with DCM, washed with dilute HCI, dried (Na2SO4) and evaporated in vacuo. Column chromatography (Siθ2, MeOH/DCM, 10:90) gave the title compound as a colourless glass (204mg). δH (DMSO-d6) (rotameric species observed) 10.87 (1H, s, CONH), 8.77 (2H, s, PyH), 7.85-7.65 (1H, m, NH), 7.56 (2H, d, A 8.6Hz, ArH), 7.39 (2H, m, ArH), 7.10-6.85 (1 H, m, NH), 5.38 (1 H, m,
ArCHNH), 4.61 (1 H, m, OH), 3.73-3.69 (3H, m, OMe), 3.55 (3H, s, OMe),
3.44 (2H, br s, CH2CH2), 3.30 (CH2CH2, peak under HOD), 2.95 (1 H, m,
CHAHBCO2Me), 2.75 (1 H, dd, CHAHBCO2Me); m/z (ES+, 70V) 536 ((MH+).
EXAMPLE 13
3-f4-rr3.5-Dichloroisonicotinovl)aminolphenvlV3-^4-r2- hvdroxvethvlamino1-6-methoxv-1.3.5-triazin-2-vnamine)propanoic acid The title compound was prepared by the method of Example 2 from the compound of Example 12 as a white solid. δH (DMSO-d6, 390K) 10.40
(1 H, br s, CONH), 8.66 (2H, s, CI2PyH), 7.55 (1 H, br, NH), 7.52 (2H, br d, ArH), 7.41 (2H, br d, A 8.5Hz, ArH), 6.36 (1 H, br m, NH), 5.40 (1 H, br m, ArCHNH), 3.76 (3H, s, OMe), 3.52 (2H, t, 6-1 Hz, NHCH2CH2CH), 3.34 (2H, q, A 5.7Hz, NHCH2CH2CH), 2.3 (1 H, br s, OH) from 300K spectrum 2.8-2.5 (2H, m, CH2CO2H); m Z (ES+, 70\/), 522 (MH+). EXAMPLE 14
Methvl 3-f4-r(3.5-dichloroisonicotinovnaminolphenvlV3-r^2S - rf3.5-dichlorophenvnsulphonvntetrahvdro-1-Ay-pvrrol-2- yDparbpnyOaminplprppanpate
EDC (158mg, 0.825mmol) was added to a mixture of Intermediate 6 (37.7mg, 0.75mmol) Intermediate 8 (243mg, 0.75mmol) HOBT (111 mg, 0.825mmol) and NMM (173μl, 1.58mmol) in DMF (5ml). The mixture was stirred at room temperature overnight then the solvent removed in vacuo. The residue was dissolved in EtOAc and washed with dilute HCI, NaHCO3 (aqueous), water and brine, dried (Na2SO4) and evaporated in vacuo. Column chromatography (Siθ2.' MeOH/DCM, 5:95) gave the title compound as a white foam (402mg). δH (DMSO-d6) (mixture of diastereoisomers) 10.90 (1 H, s, CONH), 8.78 (2H, s, CI2PyH), 8.53 (1 H, m, CHNH), both diastereoisomers), 8.00 (t, A 1.9Hz) and 7.97 (t, A 1.9Hz) together (1H, CI2ArH), 7.84 (d, J 1.9Hz) and 7.78 (d, J 1.9Hz) together (2H, CI2ArH), 7.60 (d, A 8.6Hz) and 7.59 (d, A 8.6Hz) together (2H, ArH), 7.36 (d, A 8.6Hz) and 7.34 (d, A 8.6Hz) together (2H, ArH), 5.18 (1 H, m, CHNH), 4.22-4.14 (1 H, m, CHα), 3.57 (3H, s, CO2Me), 3.45-3.35 (1 H, m, NCHAHB), 3.30 (1 H, NCHAHB), 2.95-2.75 (2H, m, CH2CO2Me), 1.95-1.60 (4H, m, NCH2CH2CH2); m/Z (ES+, 70V) 675 (MH+).
EXAMPLE 1$
3-{4-rr3.5-Dichloroisonicotinovnamino PhenylV3-. 2S -1-[(3.5- dichlorophenvnsulphonvntetrahvdro-1-A/-pvrrol-2-vl carbonvnamino1 prppanpjp acid
The title compound was prepared by the method of Example 2 from the compound of Example 14 as a white solid δH (DMSO-d6) (2 diastereoisomers) 12.3 (1 H, br s, CO2H), 10.89 (1 H, s, CONH), 8.78 (2H, s, CI2PyH), 8.53 (d, A 8.1 Hz) and 8.48 (d, A 8.1 Hz) together (1 H, CONH), 8.00 (t, A 1.9Hz) and 7.97 (t, A 1.9Hz) together (1 H, ArH), 7.85 (d, A 1.8Hz) and 7.78 (d, A 1.8Hz) together (2H, ArH), 7.61-7.57 (2H, m, ArH), 7.37-7.32 (2H, m, ArH), 5.13 (1 H, m, CHNH), 4.24-4.16 (1H, m, CHα), 3.45-3.35 (1 H, m, CHAHBN), 3.25 (1 H, CHAHBN), 2.81 (1 H, dd, 15.8, 7.5Hz, CHAHBCO2) , 2.75-2.69 (1 H, m, CHAHBCO2), 1.9-1.6 (4H, m, CH2CH2CH2N); m/z (ES+, 70V) 659 (MH+). EXAMPLE 1<?
Ethvl (2RS. 3R Si-3-M-r(3.5-dichloroisonicotinovnamino1phenyl}-3-r4- f3.5-dichloroisonicotinovnamino1-2-hvdroxvpropanoate A solution of 3,5-dichloroisonicotinoylchloride (269mg, 1.28mmol) in DCM (5ml) was added to a solution of Intermediate 10 (130mg, 0.58mmol) and NMM (140μl, 1.28mmol) in DCM (5ml). After 3.5h at room temperature the mixture was diluted with DCM and washed with dilute HCI and NaHCO3 (aqueous), dried (Na2SO4) and evaporated in vacuo. Column chromatography (Siθ2; MeOH/DCM , 7:93) gave the title compound as a white solid (198mg). δH (DMSO-d6) 10.90 (1 H, s, CONHAr), 9.56 (1H, d, A 9.0Hz, CONHCH), 8.79 (2H, s, CI2PyH2), 8.67 (2H, s, CI2PyH2), 7.58 (2H, d, A 8.6Hz, ArH), 7.38 (2H, d, A 8.6Hz, ArH), 5.88 (1 H, d, A 6.0Hz, OH), 5.35 (1 H, dd, A 9.0, 5.8Hz, NHCH), 4.32 (1 H, t, A 5.9Hz, CHOH), 4.15-4.08 (2H, m, CO2CH2CH3), 1.22 (3H, t, A 7.1 Hz, CO2CH2CH3). m/z (ES+, 70V) 573 (MH+).
EXAMPLE 17 f2 ?S.3/?S)-3-f4-rf3.5-Dichloroisonicotinovnamino1phenvl 3-[4-(3.5- ςjighlprpispnipptinpyl)aminp]-2-hyp!rpχyprppanpi agid
The title compound was prepared by the method of Example 2 from the compound of Example 16 as an off white solid. δH (DMSO-d6) 12.8 (1 H, v br s, CO2H), 10.90 (1 H, s, CONHAr), 9.54 (1 H, d, A 8.8Hz, NHCH), 8.78 (2H, s, CI2PyH2), 8.66 (2H, s, CI2PyH2), 7.57 (2H, d, A 8.4Hz, ArH), 7.39 (2H, d, 8.4Hz, ArH), 5.6 (1 H, v br s, OH), 5.37 (1 H, dd, A 8.7, 5.4Hz, NHCH), 4.26 (1H, d, A 5.3Hz, CHOH); m/z (ES+, 70V) 545 (MH+).
EXAMPLE 19
Ethvl (2RS. 3A?S)-3 4-aminoPhenvn-3-r^2S -1-r(3.5- dichlorophenvMsulphonvntetrahvdro-1- -pvrrol-2-y carbonvnamino]- 2-hvdroxvpropanoate
A mixture of Intermediate 10 (250mg, 1.12mmol), Intermediate 8 (363mg, 1.12mmol), HOBT (166mg, 1.23mmol), NMM (135μl, 1.23mmol) and EDC HCI (236mg, 1.23mmol) in DMF (5ml) and DCM (10ml) was stirred at room temperature for 3 days. The solvents were removed in vacuo. The residue was dissolved in DCM, washed with dilute HCI and NaHCO3 (aqueous), dried (Na2SO4) and evaporated in vacuo. Column chromatography (Siθ2: MeOH/DCM, 5:95) gave the title compound as a yellow oil (129mg). δH
(DMSO-d6) (mixture of diastereoisomers) 8.23 (1 H, d, A 8.7Hz, CONH), 8.00 (t, A 1.9Hz) and 7.98 (t, A 1.9Hz) together (1H, CI2ArH), 7.85 (d, A 1.9Hz) and 7.79 (d, A 1.9HZ) together (2H, CI2ArH2), 6.99 (d, A 8.4Hz) and 6.94 (d, A 8.4Hz) together (2H, ArH), 6.48-6.42 (2H, m, ArH), 5.05-4.93 (3H, m, CHα+NH2), 5.67 (d, J 5.7Hz) and 5.62 (d, J 6.1 Hz) together (1 H, OH), 4.4-4.3 (1H, m, CHNH), 4.27-4.19 (1H, m, CHOH), 4.06-3.98 (2H, m, CO2CH2CH3), 3.40-3.20 (2H, m, CH2N), 1.9-01.55 (4H, m, CHCH2CH2CH2N), 1.15 (t, A 7.1 HZ) and 1.14 (t, A 7.1 Hz) together (3H, CO2CH2CH3); m/z (ES+, 70V) 552 (MH+).
EXAMPLE 19
Ethv 2/?S.3 ?S)-3-f4r(3.5-dichloroisonicotinovnamino1phenvl>-3- fr^2S -1-rr3.5-dichlorophenvnsulphonvntetrahvdro-1-A -pyrrol-2- vncarbonvπaminoV2-hvdroxvρropanoate
A solution of 3,5-dichloroisonicotinoyl chloride (55mg, 0.259mmol) in DCM (2ml) was added to a solution of the compound of Example 18 (125mg, 0.236mmol) and NMM (28μl, 0.259mmol) in DCM (5ml). The mixture was stirred overnight at room temperature then diluted with DCM, washed with dilute HCI, dried (Na2SO4) and evaporated in vacuo. Column chromatography (Siθ2: MeOH/DCM, 6:94) gave the title compound as a yellow foam (135mg). δH (DMSO-d6) (mixture of diastereoisomers) 10.88 (1 H, s, CONH), 8.78 (2H, s, CI2PyH2), 8.50 (1 H, app. t. A 9.1 Hz, CONH), 8.01 (t, A 1.9Hz) and 7.97 (t, A 1.9Hz) together (1 H, CI2ArH), 7.84 (d, A 1.9Hz) and 7.77 (d, A 1.9Hz) together (2H, CI2ArH2), 7.58 (d, A 8.6Hz) and 7.55 (d, A 8.5Hz) together (2H, ArH), 7.35 (d, J_8.6Hz) and 7.30 (d, A 8.6Hz) together (2H, ArH), 5.89 (d, A 5.9Hz) and 5.84 (d, A 6.2Hz) together (1 H, OH), 5.14-5.07 (1H, m, CHα), 4.36-4.26 (2H, m, CHNH + CHOH), 4.11-4.04 (2H, m, CO2CH2), 3.45-3.20 (2H, m, CH2N), 1.90-1.60 (4H, m, CH2CH2CH2N), 1.20 (t, J. 7.1 Hz) and 1.19 (t, A 7.1 Hz) together (3H,
EXAMPLE 20 (2RS. 3 ?S -3-f4-r(3.5-Dichloroisonicotinovnamino1phenvn-3- r^2S)-1 -
[(3.?-p:iPhlPrppheny|)? lphPnyl]tPtrahyclrp-1-.-* -pyrrpl-2- y;)carbonvπamino>-2-hydroxvpropanoic acid
The title compound was prepared by the method of Example 2 from the compound of Example 19 as a pale brown solid. δH (DMSO-d6) (mixture of diastereoisomers) 12.7 (1 H, br s, CO2H), 10.87 (1 H, s, CONH), 8.78 (2H, s, CI2PyH2), 8.50 (d, A 8.9Hz) and 8.45 (d, A 8.8Hz) together (1 H, CONH), 8.01 (t, A 1.9Hz) and 7.96 (t, A 1.9Hz) together (1 H, CI2ArH), 7.86 (d, A 1.8Hz) and 7.78 (d, A 1.9Hz) together (2H, CI2ArH2), 7.58-7.53 (2H, m ArH), 7.35 (d, A 8.7Hz) and 7.31 (d, A 8.6Hz) together (2H, ArH), 5.64 (1 H, br m, OH), 5.16-5.09 (1 H, m, CHα), 4.42-4.20 (2H, m, CHOH + CHNH), 3.50-3.20 (2H, m, CH2N), 1.90-1.60 (4H, m, CH2CH2CH2N); m/z (ES+, 70V) 677 (MH+).
EXAMPLE 21
3-^rMS)-3-Acetvl-1.3-thiazolan-4-vncarbonvl amino 3-f4-^3.5- dichloroisonicotinovnaminolphenvltoropanoic acid
Prepared from Intermediate 6 and N-Acetyl-D-thioproline by the methods described in Examples 18 and 2. δH (DMSO-d6, 390K) (mixture of diastereoisomers) 10.41 (1 H, s, CONH), 8.69 (2H, s, CI2PyH2), 7.99 (1 H, br s, CONH), 7.59-7.57 (2H, m, ArH), 7.38-7.34 (2H, m, ArH), 5.26-5.21 (1 H, m, CHα), 4.87-4.78 (2H, m, CHNH + NCHAHBS), 4.49-4.44 (1 H, m, NCHAHBS), 3.35-3.30 (m) and 3.20-3.08 (m) and 2.87-2.64 (m) together (4H, m, CHCH2S + CH2CO2H), 2.51 (s) and 2.50 (s) together (3H, COCH3); m/z (ES+, 70V) 511 (MH+).
EXAMPLE 22
3-r{rf4/?)-3-Acetvl-1.3-thiazolan-4-vπcarbonvnamino 3-f4-r3.5- dichloroisonicotinovnaminolphenyftpropanoic acid Prepared from intermediate 6 and /V-acetyl-L-thioproline by the methods described in Examples 18 and 2. δH (DMSO-d6, 390K) (mixture of diastereoisomers) 10.41 (1 H, s, CONH), 8.69 (2H, s, CI2PyH2), 7.99 (1 H, br s, CONH), 7.59-7.57 (2H, m, ArH), 7.38-7.34 (2H, m, ArH), 5.26-5.21 (1 H, m, CHα), 4.87-4.78 (2H, m, CHNH + NCHAHBS), 4.49-4.44 (1 H, m, NCHAHBS), 3.35-3.30 (m) and 3.20-3.08 (m) and 2.87-2.64 (m) together (4H, m, CHCH2S + CH2CO2H), 2.51 (s) and 2.50 (s) together (3H, COCH3); m/Z (ES+, 70V) 511 (MH+).
EXAMPLE 23 3-f4-ff2.6-Dichlorobenzovnaminolphenvl1-3-r(cvclohexyl paτbpnyl)aminp]prppanpiQ a id
To Intermediate 14 (130mg) was added DMF (0.5ml), DIEA in DMF (1 M, 0.2ml), cyclohexanecarboxylic acid in DMF (1 M, 0.3ml) and [O-(7- azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium]hexafluorophosphate in DMF (0.5M, 0.5ml). The solution was agitated at room temperature for 10h followed by filtration and multiple washes with DMF and DCM. The resin was treated with a mixture of TFA, DCM and water (6:3:1) (3ml) for 3h with agitation and then filtered. The filtrate was evaporated in vacuo to give the crude product which was purified by preparative HPLC to afford the title compound (2mg)
HPLC-MS Retention time 3.9min; m/z (ES+, 70V) 464 (MH+).
HPLC-MS
HPLC-MS was performed on a Hewlett Packard 1100/MSD ES Single Quadrapole system with diode array detector using a Luna C18(2) 50 x 4.6mm (3 μm particle size) column, running a gradient of 95% [20mM ammonium formate, pH 3.5], 5% [0.1 % formic acid in acetonitrile] to 10% [20mM ammonium formate, pH 3.5], 90% [0.1% formic acid in acetonitrile] over 3 min, then maintaining the mobile phase at that ratio for a further 2 min. Flow rate 0.8ml/min.
The compounds of Examples 24 to 27 were prepared in a similar manner to the compound of Example 23, using Intermediate 14 and the carboxylic acid shown.
EXAMPLE 24
3-f4-r(2.6-Dichlorobenzovnamino1phenvlV3-{r2-(3- pvridinvnacewπaminolpropanoic acid
3-Pyridylacetic acid gave the title compound (4mg) HPLC-MS Retention time 3.2m in; m/z (ES+, 70V) 472 (MH+). EXAMPLE 25 3-{4-[(2,g-PiPhlprpb. enzpy|)aminp]phPnyl}-3-[({2-[(2.$- dimethoxvphenvnthio1-3-pvridinvl, carbonvnamino1propanoic acid
2-(2,5-Dimethoxyphenylthio)-3-pyridine carboxylic acid gave the tjtje compound (5mg)
HPLC-MS Retention time 3.9min; m/z. (ES+, 70V) 626 (MH+).
EXAMPLE 26 3-f4-r(2.6-DichlorobenzovnaminolphenvlV3-rr3.3- dim9thylb. titanpyl)aminp]prppanpic acid
3,3-Dimethylbutanoic acid gave the title compound (2mg) HPLC-MS Retention time 3.9min; m/z (ES+, 70V) 451 (MH+).
The compounds of Examples 27 - 47 were prepared in a similar manner to the compound of Example 23 using Intermediate 13 and the starting material shown.
EXAMPLE 27 3-M-rf3.5-Dichloroisonicotinovnamino1phenvlV3-r^2-r-2.5- dimethoxvphenvnthiol-3-pvridinvncarbonvnaminolpropanoic acid
2-(2,5-dimethoxyphenylthio)-3-pyridine carboxylic acid gave the title compound (4mg)
HPLC-MS Retention time 3.7min; m/z (ES+, 70V) 627 (MH+).
EXAMPLE 28
3-{4-f(3.5-Dichloroisonicotinoyl)amino1phenvπ-3-ff(2-chloro-3- pyridinyl)carbonyl')amino}propanoic acid
2-Chloronicotinic acid gave the title compound (7mg) HPLC-MS Retention time 3.4min; m/z (ES+, 70V) 493 (MH+).
EXAMPLE 29
3-{4-f(3.5-Dichloroisonicotinoyl)amino1phenylV3-4f -(4- chlorophenvπcvclopentyl1carbonvBamino)propanoic acid 1-(4-Chlorophenyl)-1-cyclopentanecarboxylic acid gave the title compound (3mg)
HPLC-MS Retention time 4.3min; m/z (ES+, 70V) 560 (MH+). EXAMPLE 3Q
3-f4-fr3.5-Dichloroisonicotinovnamino1phenvn-3-rr(E 3-phenvl-2- propenovπaminoipropanoic acid trans-Cinnamic acid gave the title compound (4mg)
HPLC-MS Retention time 3.8min; m/z (ES+, 70V) 484 (MH+).
EXAMPLE 31
3-f4-^3.5-Dichloroisonicotinovnamino1phenvlV3-rf4- phenvlbutanovnamino^propanoic acid
4-Phenylbutanoic acid gave the title compound (3mg) HPLC-MS Retention time 3.8min; m/z (ES+, 70V) 500 (MH+).
EXAMPLE 32 3-{4-rf3.5-Dichloroisonicotinovnamino1phenvll-3-rf4- piperidinvlcarbonvnaminolpropanoic acid
Isonipecotic acid gave the title compound (3mg)
HPLC-MS Retention time 2.9min; m/z (ES+, 70V) 465 (MH+).
EXAMPLE 33
3-f4-rf3.5-Dichloroisonicotinovnamino1phenvlV3-frf4.β-dimethvl-2- oxo-2H-pvran-5-vMcarbonvηamino propanoic acid
Isodehydracetic acid gave the title compound (2mg) HPLC-MS Retention time 3.4m in; rnlz (ES+, 70V) 504 (MH+).
EXAMPLE 34
3-f4-r(3.5-DichloroisonicotinovnaminoΪPhenvlV3- rfcvclobutvlcarbonvnaminolpropanoic acid Cyclobutanecarboxylic acid gave the title compound (1 mg) HPLC-MS Retention time 3.6min; m/z (ES+, 70V) 436 (MH+).
EXAMPLE 35
3-f4-r/3.5-Dichloroisonicotinovl amino1phenvlV3- rfcvclopropvlcarbonvnaminolpropanoic acid Cyclopropanecarboxylic acid gave the title compound (1 mg) HPLC-MS Retention time 3.5min; m/z (ES+, 70V) 422 (MH+). EXAMPLE 36
3-f4-ff3.5-Dichloroisonicotinovnamino1phenvlV3- 3- methvlcvclohexvncarbonvnaminotoropanoic acid 3-Methyl-1-cyclohexanecarboxylic acid gave the title compound (2mg) HPLC-MS Retention time 4.0min; m/z (ES+, 70V) 478 (MH+).
EXAMPLE 37
3-{4-f(3.5-DichloroisonicotinovnaminolphenvlV3-{[(4- methvlcvclohexvncarbonvπamino^propanoic acid
4-Methyl-1-cyclohexanecarboxylic acid gave the title compound (2mg) HPLC-MS Retention time 4.0min; m/z (ES+, 70V) 478 (MH+).
EXAMPLE 39 3-f4-ff3.5-Dichloroisonicotinovnamino1phemm-3-ff3.3- dimethvlbutanovnaminolpropanoic acid
3,3-Dimethylbutanoic acid gave the title compound (5mg) HPLC-MS Retention time 3.7min; m/z (ES+, 70V) 452 (MH+).
EXAMPLE 39
3-f4-ff3.5-DichloroisonicotinovMamino1phenvl 3-ffr5-f2-pvrazinvl 1.3- thiazol-2-vπcarbonvl amino)propanoic acid
5-(2-Pyrazinyl)-2-thiazolylcarboxylic acid gave the title compound (2mg) HPLC-MS Retention time 3.7m in; m/z (ES+, 70V) 453 (MH+).
EXAMPLE 4Q 3-f4-ff3.5-Dichloroisonicotinovnamino1phenvlV3-fff1-methvl-5-nitrp-
1 H-pyra2Pl-4-yl)garbpnyl]aminp}prppanpip acid
1-Methyl-5-nitropyrazole-4-carboxylic acid gave the title compound (3mg) HPLC-MS Retention time 3.6min; m/z (ES+, 70V) 507 (MH+).
EXAMPLE 41
3-f4-rf3.5-Dichloroisonicotinovnamino,)phenvlV3-fff4-methvl-1.2.3- thiadiazol-5-vncarbonvr|aminoϊpropanoic acid 4-Methyl-1 ,2,3-thiadiazole-5-carboxylic acid gave the title compound (3mg) HPLC-MS Retention time 3.6min; m/z. (ES+, 70V) 480 (MH+). EXAMPLE 42
3-{4-ff3.5-Dichloroisonicotinovnamino1phenvn-3-ff2.1.3- benzoxadiazol-4-vlcarbonvnaminolpropanoic acid Benzofurazan-5-carboxylic acid gave the title compound (3mg) HPLC-MS Retention time 3.8min; m/z (ES+, 70V) 500 (MH+).
EXAMPLE 43
3-f4-rf3.5-Dichloroisonicotinovnamino)phenvn-3-{ff1-ethvl-3-methvl- 1 H-pvrazol-5-vncarbonvllaminoϊpropanoic acid
1 -Ethyl-3-methyl-1 H-pyrazole-5-carboxylic acid gave the title compound
(3mg)
HPLC-MS Retention time 3.6min; m/z (ES+, 70V) 490 (MH+).
EXAMPLE 44
3-f4-rf3.5-Dichloroisonicotinovnamino phenvn-3-ff(1- pheny|gyp|pprppyl)parbpnyl]aminp}propanpip agid
1-Phenyl-1 -cyclopropanecarboxylic acid gave the title compound (4mg) HPLC-MS Retention time 3.9min; m/z (ES+, 70V) 498 (MH+).
EXAMPLE 45
3-f4-rf3.5-Dichloroisonicotinovnamino1phenvlV3-fff1-f4- chlorophenvncvclopentvπcarbonvnamino^propanoic acid
1-(4-Chlorophenyl)-1 -cyclopropanecarboxylic acid gave the title compound (5mg)
HPLC-MS Retention time 4.1 min; m/z (ES+, 70V) 532(MH+).
EXAMPLE 46
3-f4-ff3.5-DichloroisonicotinovnaminolPhenvn-3- fpropanovlaminotoropanoic acid
Propanoic acid gave the title compound (2mg)
HPLC-MS Retention time 3.4min; m/z (ES+, 70V) 410 (MH+).
EXAMPLE 47 3-f4-rf3.5-Dichloroisonicotinovnaminolphenvn-3-ff2-f3- pvridinvnacetvnaminolpropanoic acid 3-Pyridylacetic acid gave the title compound (3mg) HPLC-MS Retention time 3.1 m in; m/z (ES+, 70V) 473 (MH+).
EXAMPLE 48 3-f4-frf2.5-Dichlorophenvnsulphonvnamino,Vphenvn-3-f(3.5- dichloroisonicotinovnamino'Vpropanoic acid
To Intermediate 12 (200mg) was added 2,5-dichlorobenzenesulfonyl chloride (98mg, 0.4mmol) in pyridine (10ml). The solution was agitated at room temperature for 12h followed by filtration and multiple washes with DMF and DCM. The resin was treated with a 20% solution of piperidine in DMF (10ml) for 30min at room temperature then filtered and washed as before.
To this resin was added DIEA (70μl, 0.4mmol) and 3,5-dichloroisonicotinoyl chloride (84μl, 0.4mmol) in DCM (10ml) and the solution agitated for 12h at room temperature followed by filtration and washes with DMF and DCM. The resin was treated with a 60% solution of TFA in DCM (5ml) for 3h with agitation at room temperature and then filtered. The filtrate was evaporated in vacuo to give the crude product which was purified by preparative HPLC to afford the title compound (3mg). HPLC-MS Retention time 3.9min; m/z. (ES+, 70V) 563 (MH+).
EXAMPLE 49
3-f4-ff3.5-DichloroisonicotinovnaminolphenvlV3-frf3.4- dichloroanilino)carbonvl]amino>propanoic acid To Intermediate 12 (200mg) was added DIEA (70μl, 0.4mmol) and 3,5- dichloronicotinoyl chloride (70μl , 0.4mmol) in DCM (10ml). The solution was agitated at room temperature for 12h followed by filtration and multiple washes with DMF and DCM. The resin was treated with a 20% solution of piperidine in DMF (10ml) for 30min at room temperature then filtered and washed as before.
To this resin was added DIEA (70μl, 0.4mmol) and 3,4-dichloro- phenylisocyanate (75mg, 0.4mmol) in DCM (10ml) and the solution agitated for 12h at room temperature followed by filtration and washed with DMF and DCM. The resin was treated with a 60% solution of TFA in DCM (5ml) for 3h with agitation at room temperature and then filtered. The filtrate was evaporated in vacuo to give the crude product which was purified by preparative HPLC to afford the title compound (2mg) HPLC-MS Retention time 4.7min; m/z (ES+, 70V) 542 (MH+).
EXAMPLE 50
3-f4-fff3.4-Dichloroanilino^carbonvπamino^phenvn-3-ff3.5- dichloroisonicotinovnaminolpropanoic acid
To Intermediate 12 (200mg) was added DIEA (70μl, 0.4mmol) and 3,4- dichlorophenylisocyanate (75mg, 0.4mmol) in DCM (10ml) and the solution agitated for 12h at room temperature followed by filtration and washes with DMF and DCM. The resin was treated with a 20% solution of piperidine in DMF (10ml) for 30min at room temperature then filtered and washed as before. To this resin was added DIEA (70μl, 0.4mmol) and 3,5-dichloronicotinoyl chloride (84μl, 0.4mmol) in DCM (10ml) and the solution agitated for 12h at room temperature followed by filtration and washes with DMF and DCM. The resin was treated with a 60% solution of TFA in DCM (5ml) for 3h with agitation at room temperature and then filtered. The filtrate was evaporated in vacuo to give the crude product which was purified by preparative HPLC to afford the title compound (5mg)
HPLC-MS Retention time 4.1 min; m/z (ES+, 70V) 542 (MH+).
The following assays can be used to demonstrate the potency and selectivity of the compounds according to the invention. In each of these assays an IC50 value was determined for each test compound and represents the concentration of compound necessary to achieve 50% inhibition of cell adhesion where 100% = adhesion assessed in the absence of the test compound and 0% = absorbance in wells that did not receive cells.
96 well NUNC plates were coated with F(ab)2 fragment goat anti-human IgG Fcγ-specific antibody [Jackson Immuno Research 109-006-098: 100 μl at 2 μg/ml in 0.1 M NaHCO3, pH 8.4], overnight at 4°. The plates were washed (3x) in phosphate-buffered saline (PBS) and then blocked for 1 h in PBS/1 % BSA at room temperature on a rocking platform. After washing (3x in PBS) 9 ng/ml of purified 2d VCAM-lg diluted in PBS/1 % BSA was added and the plates left for 60 minutes at room temperature on a rocking platform. The plates were washed (3x in PBS) and the assay then performed at 37° for 30 min in a total volume of 200 μl containing 2.5 x 105 Jurkat cells in the presence or absence of titrated test compounds.
Each plate was washed (2x) with medium and the adherent cells were fixed with 100μl MeOH for 10 minutes followed by another wash. 100μl 0.25%
Rose Bengal (Sigma R4507) in PBS was added for 5 minutes at room temperature and the plates washed (3x) in PBS. 100μl 50% (v/v) EtOH in PBS was added and the plates left for 60min after which the absorbance (570nm) was measured.
α^βj Inteαrin-dependent JY cell adhesion to MAdCAM-lq This assay was performed in the same manner as the α4βι assay except that MAdCAM-lg (150ng/ml) was used in place of 2d VCAM-lg and a sub- line of the β-lympho blastoid cell-line JY was used in place of Jurkat cells. The IC50 value for each test compound was determined as described in the α-vβi integrin assay.
αsβ^ Inteαrin-dependent K562 cell adhesion to fibronectin
96 well tissue culture plates were coated with human plasma fibronectin (Sigma F0895) at 5μg/ml in phosphate-buffered saline (PBS) for 2 hr at 37°C. The plates were washed (3x in PBS) and then blocked for 1 h in 100μl PBS/1 % BSA at room temperature on a rocking platform. The blocked plates were washed (3x in PBS) and the assay then performed at 37°C in a total volume of 200μl containing 2.5x 105 K562 cells, phorbol-12- myristate-13-acetate at 10ng/ml, and in the presence or absence of titrated test compounds. Incubation time was 30 minutes. Each plate was fixed and stained as described in the α.4βι assay above.
αmβ2-dependent human polymorphonuclear neutrophils adhesion to plastic
96 well tissue culture plates were coated with RPMI 1640/10% FCS for 2h at 37°C. 2 x 105 freshly isolated human venous polymorphonuclear neutrophils (PMN) were added to the wells in a total volume of 200μl in the presence of 10ng/ml phorbol-12-myristate-13-acetate, and in the presence or absence of test compounds, and incubated for 20min at 37°C followed by 30min at room temperature. The plates were washed in medium and 100μl 0.1 % (w/v) HMB (hexadecyl trimethyl ammonium bromide, Sigma H5882) in 0.05M potassium phosphate buffer, pH 6.0 added to each well. The plates were then left on a rocker at room temperature for 60 min. Endogenous peroxidase activity was then assessed using tetramethyl benzidine (TMB) as follows: PMN lysate samples mixed with 0.22% H2O2 (Sigma) and 50μg/ml TMB (Boehringer Mannheim) in 0.1 M sodium acetate/citrate buffer, pH 6.0 and absorbance measured at 630nm.
αllb/βs -dependent human platelet aααreαation
Human platelet aggregation was assessed using impedance aggregation on the Chronolog Whole Blood Lumiaggregometer. Human platelet-rich plasma (PRP) was obtained by spinning fresh human venous blood anticoagulated with 0.38% (v/v) tri-sodium citrate at 220xg for 10 min and diluted to a cell density of 6 x 108/ml in autologous plasma. Cuvettes contained equal volumes of PRP and filtered Tyrode's buffer (g/liter: NaCI 8.0; MgCI2.H2O 0.427; CaCI2 0.2; KCl 0.2; D-glucose 1.0; NaHCO3 1.0; NaHPO4.2H2O 0.065). Aggregation was monitored following addition of 2.5μM ADP (Sigma) in the presence or absence of inhibitors.
In the above assays the preferred compounds of the invention generally have IC50 values in the α4βι and α4βγ assays of 1 μM and below. In the other assays featuring integrins of other subgroups the same compounds had IC50 values of 50μM and above thus demonstrating the potency and selectivity of their action against 0:4 integrins.

Claims

1. A compound of formula (1 ):
Ar1 (Alk )rL1Ar2CH(R1 )C(Ra)(Ra')R (1 ) wherein
Ar1 is an optionally substituted aromatic or heteroaromatic group; L1 is a covalent bond or a linker atom or group selected from -CON(R2)- [where R2 is a hydrogen atom or a Ci -3alkyl group], -SO2N(R2)-, -C(O)O-, -N(R2)- or -O-;
Ar2 is an optionally substituted phenylene or nitrogen-containing six- membered heteroarylene group;
R1 is a group selected from -NHCOR3 [where R3 is an optionally substituted aliphatic, heteroaliphatic, cycloaliphatic, polycycloaliphatic, heterocycloaliphatic, heteropolycycloaliphatic, aromatic or heteroaromatic group], -NHSO2R3, -NHR3, -NHC(O)OR3, -NHCSR3, -NHCON(R3)(R3a) [where R3a is a hydrogen atom or a group R3 and R3 and R3 a are the same or different], -NHSO2N(R3)(R3a), -NHCSN(R3)(R3a), -CON(R3)(R3a) or -CSN(R3)(R3a); Ra and Ra' which may be the same or different is each independently selected from a hydrogen or halogen atom or an optionally substituted straight or branched alkyl, alkenyl or alkynyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, or -(Alk )mRb group (in which Alkb is a C-|. 3alkylene chain, m is zero or the integer 1 and Rb is a -OH, -SH, -NO2, -CN, -CO2H, -CO2Rc, (where Rc is an optionally substituted straight or branched Cι-6alkyl group), -SO3H, -SORc, -SO2Rc, -SO3Rc, -OCO2Rc, -C(O)H, -C(O)Rc, -OC(O)Rc, -C(S)RC, -NRdRe [where Rd and Re which may be the same or different is each a hydrogen atom or an optionally substituted straight or branched alkyl group], -C(O)N(Rd)(Re), -OC(O)N(Rd)(Re), -N(Rd )C(O)Re,
-CSN(Rd)(Re), -N(R)d C(S)Re, -SO2N(Rd)(Re), -N(Rd)SO2Re,
-N(Rd)CON(Re)(Rf) [where Rf is a hydrogen atom or an optionally substituted straight or branched alkyl group], -N(Rd)C(S)N(Re)(R ) or -N(Rd)SO2N(Re)(Rf) group). Alka is an optionally substituted aliphatic or heteroaliphatic chain; r is zero or the integer 1 ;
R is a carboxylic acid (-CO2H) or a derivative thereof; and the salts, solvates, hydrates and N-oxides thereof.
2. A compound according to Claim 1 in which R is a -CO2H group.
3. A compound according to any one of Claims 1 to 2 in which Ra' is a hydrogen atom.
4. A compound according to any one of Claims 1 to 3 in which Ra is a hydrogen atom or a hydroxyl group.
5. A compound according to any one of Claims 1 to 4 in which (Alka)rL1 is a -CON(R2)- group.
6. A compound according to Claim 5 in which (Alka)rL1 is a -CONH- group.
7. A compound according to any one of Claims 1 to 6 in which Ar2 is an optionally substituted 1 ,4-phenylene group.
8. A compound according to Claim 7 in which Ar2 is a 1 ,4-phenylene group.
9. A compound according to any one of Claims 1 to 8 in which Ar1 is an optionally substituted pyrimidinyl, pyridyl or phenyl group.
10. A compound according to Claim 9 in which Ar1 is an optionally substituted pyridyl or phenyl group.
11. A compound according to Claim 10 in which Ar1 is a 3,5- dichloropyridin-4-yl group.
12. A compound according to any one of Claims 1 to 11 in which R1 is the group -NHCOR3 or -NHR3.
13. A compound according to Claim 12 in which R3 is an optionally substituted pyrrolidinyl, thiazolidinyl, phenyl, pyrimidinyl or 1 ,3,5- triazinyl group.
14. A compound which is:
3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-3-({4-[2-hydroxyethyl- amino]-6-methoxy-1 ,3,5-triazin-2-yl}amine)propanoic acid;
3-[(3,5-Dichloroisonicotinoyl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)- amino]phenyl}propanoic acid; 3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-3-[(2,6- dimethoxybenzoyl)amino]propanoic acid;
3-({[(4S)-3-Acetyl-1 ,3-thiazolinan-4-yl]carbonyl}amino-3-{4-[(3,5- dichloroisonicotinoyl)amino]phenyl}propanoic acid;
3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-3-[({(2S)-1-[(3,5- dichlorophenyl)sulphonyl]tetrahydro-1 -H-pyrrol-2-yl}carbonyl) amino]propanoic acid;
(2RS,3RS)-3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-3-{[((2S)-1-
[(3,5-dichlorophenyl)sulphonyl]tetrahydro-1-H-pyrrol-2- yl)carbonyl]am ino}-2-hydroxypropanoic acid; 3-{4-[(3,5-Dichloroisonicotinoyl)amino]phenyl}-3-[({2-[(2,5- dimethoxyphenyl)thio]-3-pyridinyl}carbonyl)amino]propanoic acid; and the salts, solvates, hydrates and N-oxides thereof.
15. A pharmaceutical composition comprising a compound according to Claim 1 together with one or more pharmaceutically acceptable carriers, excipients or diluents.
EP99973020A 1998-11-30 1999-11-29 Beta-alanine derivatives as alpha 4 integrin inhibitors Withdrawn EP1135371A1 (en)

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